Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

December 21, 2013 by larryhbern

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Image created by Adina Hazan 06/30/2021

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival. 

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/advanced-medicineprize2013.pdf

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/18/physiologist-professor-lichtstein-chair-in-heart-studies-at-the-hebrew-university-elected-dean-of-the-faculty-of-medicine-at-the-hebrew-university-of-jerusalem/

4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

• Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock

Aviva Lev-Ari, PhD, RN

• Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Aviva Lev-Ari, PhD, RN

•  Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

• Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

See References to articles at the end of this article on

• ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

• Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux

• Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

• Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
• single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
• ion channels acting in vascular smooth muscle and/or
• endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

• the whole coding region of KCN5A gene (Kv1.5 channel).

The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

• to identify individuals at relatively low-risk for cardiovascular disease
  
• an independent protective role of the
  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy  e-mail:francesco.fedele@uniroma1.it
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4
This article is published with open access at Springerlink.com

Abstract

Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

• a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

• activity of specific ion-channels, and
• key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

• ion-channels expressed in the coronary vasculature and the possible
• correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

• analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

• polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

• IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

• influencing the susceptibility for microvascular dysfunction and (IHD,
• independent of the presence of classic cardiovascular risk factors: atherosclerosis   

http//dx.dio.org/10.1007/s00395-013-0387-4

Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease

 Introduction

Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

• endothelial dysfunction and
• atherosclerosis [11, 53, 65, 67].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

• atherosclerotic disease and
• myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

• endothelial,
• nervous,
• neurohumoral,
• myogenic, and
• metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

• ATP-sensitive potassium (KATP) channels,
• voltage-gated potassium (Kv) channels,
• voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

• coronary smooth muscle and endothelial cells, which
• modulates the degree of contractile tone in vascular muscle and
• the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

• the endothelium and vascular smooth muscle cells of coronary arterioles
• to the perpetually fluctuating demands of the myocardium for blood flow
  [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

• the clinical relevance and 
• causes of microvascular dysfunction in IHD. 

By altering the overall

• regulation of blood flow in the coronary system,
• microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

• contribute to microvascular dysfunction [29, 60]. But
• ion channels play a critical role in microvascular endothelial
• and smooth muscle function.
  

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

• microvascular dysfunction and 
• myocardial ischemia, 

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

• IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
• ion channels acting in vascular smooth muscle and/or
• endothelial cells of coronary arteries.

Discussion

Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

• In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
• In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
• The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

• hypertension = 17 %,
• T2DM = 34.1 %,
• dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

• rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
• and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

• inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
• rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

• confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

• to identify individuals at relatively low-risk for cardiovascular disease,
• regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

• endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

• NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via

• activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

• an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
• association of this SNP with CAD in Asian populations [74]. In addition,
• this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

• variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].

Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

• high-grade coronary stenosis or occlusion [19].

As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells

• potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].

Several types of K+ channels are expressed in the coronary tree.

• The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
  [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
• Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.

K-ATP channel activation results in an outward flux of potassium and

• consequent hyperpolarization, resulting in
• voltage-gated calcium channel closure,
• decreased Ca2+ influx, and ultimately
• vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

• an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

• structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

• concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

• may have originated in a common ancestor, further indicating a
• possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

• rs5215_GG against developing CAD and
• a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
• The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
  the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening

• are both impaired in diabetes mellitus [39].

It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,

• independent of the presence of either diabetes mellitus or dyslipidemia.

These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,

• regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

• future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

• pergolide [25],
• 4-amino-pyridine [32], and
• correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

• cardiac metabolic demand and
• coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

• the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

• our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

• catalyzes the hydrolysis of ATP coupled with the
• translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

• genetic variants of SERCA and the
• prevalence of microvascular dysfunction or IHD.

Conclusions

This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients

• with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.

Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

• the precise manners by which specific genetic polymorphisms affect ion channel function and expression

have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.

2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.

3. There is a lack of ethnic diversity of our cohort.

4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.

5. There is a lack of functional characterization of the described genetic polymorphisms.

6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

• sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
• in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

• typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).

Methods

In this prospective, observational, single-center study – 242 consecutive patients admitted to our department were enrolled with

• the indication to undergo coronary angiography .

All patients matched inclusion criteria

1. age [18];
2. suspected or documented diagnosis of acute coronary syndrome or stable angina
3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

1. previous allergic reaction to iodine contrast,
2. renal failure,
3. simultaneous genetic disease,
4. cardiogenic shock,
5. non- ischemic cardiomyopathy

All patients signed an informed consent document  –

prior to participation in the study, which included

• acknowledgement of the testing procedures to be performed
  (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

1. both endothelium-dependent microvascular function
   [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
2. nonendothelium-dependent microvascular function
   [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

• the 242 patients were divided into three groups (see also Fig. 1).

1. Group 1: 155 patients with anatomic coronary alteration
   (comprising patients with acute coronary syndrome and chronic stable angina).
   • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
   • after IC infusion of acetylcholine and adenosine].
2. Group 2: 46 patients with functional coronary alteration
   [normal coronary arteries as assessed by angiography, and
   • as assessed by angiography and with normal functional tests
     (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
3. Group 3: 41 patients with anatomically and functionally normal coronary arteries

 

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

• related to ion channels and/or reported to be associated with
• microvascular dysfunction and/or myocardial ischemia and/or
• diseases correlated to IHD, such as diabetes mellitus.

Polymorphisms for the following genes were analyzed:

1. NOS3 (endothelial nitric oxide synthase, eNOS),
2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
3. SCN5A (voltage-dependent Na+ channel,
4. Nav1.5),
5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

• exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
• the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
• four previously described variants [26, 47, 71, 72].

We also examined

• the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

• the prevalence of SNPs in genes encoding  several effectors (including ion channels)
• involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

• a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
  undergoing coronary angiography,

we estimated that

• a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
  • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

• analysis of multiple inheritance models for SNPs were also tested
  (co-dominant, dominant, recessive, over-dominant and log-additive)
• using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
• designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

• with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

• the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
• using a free web-based application  (http://213.151.99.166/index.php?module=Snpstats) [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

• were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

• one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

• the independent impact of genetic polymorphisms on
  • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

• genetic polymorphisms on coronary artery disease
  and microvascular dysfunction,

while adjusting for other confounding variables.  The following parameters were entered into the model:

• age,
• male gender,
• type 2 diabetes mellitus (T2DM),
• systemic arterial hypertension,
• dyslipidemia,
• smoking status, and
• family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

• into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

• fasting levels of glucose of >126 mg/dL in two separate measurements or
• if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

• systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
• in two separate measurements or
• if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

• serum cholesterol levels were>220 mg/dL or
• if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.

Results

Sixty-two polymorphisms distributed among six genes coding for

• nitric oxide synthase,
• the SERCA pump, and
• ion channels
  • were screened for sequence variations using PCR amplification and
  • direct DNA sequencing analysis

in the population of

• 155 patients with CAD (group 1),
• 46 patients with microvascular dysfunction (group 2), and
• 41 patients with normal coronary arteries and
  • normal endothelium dependent and endothelium-independent vasodilation (group 3).

In Group 3, the genotype distribution of

• SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).

In Group 1 (CAD), the polymorphism

• rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).

The genotypic distribution of groups in terms of polymorphisms for

• eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5

were noticed. However, significant differences (p.05) for the SNPs

• rs5215_GG, and
• rs5219_AA of Kir6.2/KCNJ11 were observed,

as shown in Table 2. 

Table 3 displays significant differences between normal subjects (group 3) and

• patients with either CAD (group 1) or microvascular dysfunction (group 2).

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

• significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
• a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

• in microvascular dysfunction for rs5219 AA. In contrast,
• rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

SOURCE for TABLES

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

REFERENCES

1. Alekseev AE, Hodgson DM, Karger AB, Park S, Zingman LV, Terzic A (2005) ATP-sensitive K? channel channel/enzyme multimer: metabolic gating in the heart. J Mol
Cell Cardiol 38:895–905. doi:10.1016/j.yjmcc.2005.02.022
2. Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, Siffert W (1999) G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on
alpha(2)-adrenoceptor activation. Circ Res 85:965–969. doi:10.1161/01.RES.85.10.965
3. Belardinelli L, Shryock JC, Fraser H (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor
ranolazine. Heart 92:6–14. doi:10.1136/hrt.2005.078790
4. Berwick ZC, Moberly SP, Kohr MC, Morrical EB, Kurian MM, Dick GM, Tune JD (2012) Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-
flow autoregulation. Basic Res Cardiol 107:264. doi:10.1007/s00395-012-0264-6
5. Brayden JE (2002) Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 29:312–316. doi:10.1046/j.1440-1681.2002.03650.x
6. Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378. doi:10.1152/physrev.00032.2008
7. Chen TT, Luykenaar KD, Walsh EJ, Walsh MP, Cole WC (2006) Key role of Kv1 channels in vasoregulation. Circ Res 99:53–60. doi:10.1161/01.RES.0000229654.45090.57
8. Cohen KD, Jackson WF (2005) Membrane hyperpolarization is not required for sustained muscarinic agonist-induced increases in intracellular Ca2+ in arteriolar endothelial
cells. Microcirculation 12:169–182. doi:10.1080/10739680590904973
9. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gu¨nter K, Goedel-Meinen L (1990) Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium
channels. Science 247:1341–1344. doi:10.1126/science.2107575
10. Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141. doi:10.1161/01.RES.0000261970.18328.1d
…. 75

SOURCE for References 1-75

Basic Res Cardiol (2013) 108:387   http://dx.doi.org/10.1007/s00395-013-0387-4

Other related articles published on this Open Access Online Scientific Journal include the following: 

ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

Calcium Role in Cardiovascular Diseases

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
and
Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Reversal of Cardiac Mitochondrial Dysfunction

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Calcium Signaling, Cardiac Mitochondria and Metabolic Syndrome

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/11/09/calcium-signaling-cardiac-mitochondria-and-metabolic-syndrome/

Mitochondrial Dysfunction and Cardiac Disorders

Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

Mitochondrial Metabolism and Cardiac Function

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix Identified

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

Mitochondrial Dynamics and Cardiovascular Diseases

Ritu Saxena, Ph.D.

http://pharmaceuticalintelligence.com/2012/11/14/mitochondrial-dynamics-and-cardiovascular-diseases/

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis -with a Concomitant Influence on Mitochondrial Function

Larry H. Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/01/mitochondrial-mechanisms-of-disease-in-diabetes-mellitus/

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “Powerhouse of the Cell”

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading...

Posted in Cardiovascular Pharmacogenomics, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Ionic Transporters Na+, K, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics | Tagged ATO2A@, ATPase, Aviva Lev-Ari, CAD, Coronary artery disease, Coronary circulation, coronary microvascular dysfunction, eNOS, genetic polymorphisms, Heart disease, Heart Failure, Hebrew University of Jerusalem, ion channels, ischemic heart diases (IHD), KCN5A gene (Kv1.5 channel), Kir6, Myocardial Ischemia, Nav 1.5, non-modifiable protective factor, NOS encoding, rs5215_GG, rs5219_AA, SCN5A, Thomas C. Südhof, voltage-gated K ion channel | Leave a Comment »

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

December 18, 2013 by 2012pharmaceutical

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

Professor David Lichtstein Elected Dean of Hebrew University’s Faculty of Medicine

December 2, 2013

Jerusalem — Professor David Lichtstein has been elected dean of the Faculty of Medicine at The Hebrew University of Jerusalem. Professor Lichtstein is the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He replaces Professor Eran Leitersdorf, who recently completed his four-year term as dean.

According to Professor Lichtstein, “The Hebrew University’s Faculty of Medicine is devoted to creating innovative teaching, research and patient care programs that will meet the demands of 21st century health care. As global health care moves toward prevention, wellness and cost effectiveness, we are adapting how we train the next generation of physicians, nurses, pharmacists and biomedical researchers. Through fruitful collaborations between preclinical and clinical faculty, we are also translating basic biomedical insights into clinical treatments. Thus, the Faculty of Medicine is well-positioned to maintain its leading role in the scientific community of Israel and the world.”

Professor Lichtstein was born in Lodz, Poland, and immigrated to Israel with his family in 1957. As a student at The Hebrew University, he completed a Bachelor’s degree in Physiology and Zoology in 1970, followed by a Master’s degree in Physiology in 1972 and a Ph.D. in Physiology in 1977. He joined the Department of Physiology of The Hebrew University-Hadassah Medical School in 1980 as a lecturer, and received full professorship in 1994. Prof. Lichtstein has held many roles at The Hebrew University and its Faculty of Medicine, including Chairman of the Neurobiology Teaching Division, Chairman of the Department of Physiology, Chairman of the Institute for Medical Sciences and, until recently, Chairman of the Faculty of Medicine. From 2007 to 2011, Professor Lichtstein was the Jacob Gitlin Chair in Physiology at The Hebrew University. In 2011 he was named the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He also served as the President of the Israel Society for Physiology and Pharmacology from 1996 to 1999.

From 1977-1979 Professor Lichtstein was a Postdoctoral Fellow at the Roche Institute of Molecular Biology in New Jersey. He was a visiting scientist at the National Institute of Child Health and Human Development (1985-1986) and the Eye Institute (1997-1998) at the National Institutes of Health in Maryland, and a visiting professor at the Toledo School of Medicine in Ohio (2007).

Professor. Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that were known to be present in plants and amphibians are actually normal constituents of the human body and have crucial roles, such as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

SOURCE

http://www.afhu.org/professor-david-lichtstein-elected-dean-hebrew-universitys-faculty-medicine

Field of Study

Regulation of ion transport across the plasma membrane:

The primary focus of the research in my laboratory is the regulation of ion transport across the plasma membrane of eukaryotic cells. In particular, we study the main transport system for sodium and potassium, the sodium-potassium-ATPase, and its regulation by cardiac steroids.

Specific areas of interest:

Identification of endogenous cardiac steroids in mammalian tissue; The biological consequences of the interaction of cardiac steroids with the sodium-potassium-ATPase; Biosynthesis of the cardiac steroids in the adrenal gland; Effects of endogenous sodium-potassium-ATPase inhibitors on cell differentiation; Determination of the levels of endogenous sodium-potassium-ATPase inhibitors in pathological states, including hypertension, preeclampsia; malignancies (cancer) and manic depressive illnesses; Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders; Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function; Involvement of intestinal signals in the regulation of phosphate homeostasis; Volume regulation and its involvement in the mitogenic response.

Cardiac Steroids and the Na+, K+-ATPase and Cardiac Steroids

Cardiac steroids, such as ouabain, digoxin and bufalin are hormones synthesized by and released from the adrenal gland and the hypothalamus. These compounds, the structure of which resembles that of plant and amphibian and butterfly steroids, interact only with the plasma membrane Na+, K+-ATPase (Figure 1). This interaction elicits numerous specific biological responses affecting the function of cells and organs.

Topics Currently under investigation include

Cardiac Steroids

• Ouabain
• Bufalin
• Dogoxin

Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders

Depressive disorders, including major depression, dysthymia and bipolar disorder, are a serious and devastating group of diseases that have a major impact on the patients’ quality of life, and pose a significant concern for public health. The etiology of depressive disorders remains unclear. The Monoaminergic Hypothesis, suggesting that alterations in monoamine metabolism in the brain are responsible for the etiology of depressive disorders, is now recognized as insufficient to explain by itself the complex etiology of these diseases. Data from our and other laboratories has provided initial evidence that endogenous cardiac steroids and their only established receptor, the Na+, K+-ATPase, are involved in the mechanism underlining depressive disorders, and BD in particular. Our study (Biol. Psychiatry. 60:491-499, 2006) has proven that Na+, K+-ATPase and DLC are involved in depressive disorders particularly in manic-depression. We have also shown that specific genetic alterations in the Na+, K+-ATPase α isoforms are associated with bipolar disorders (Biol. Psychiatry, 65:985-991, 2009). Our recent study in this project (Eur. Neuropsychopharmacol. 22:72-729, 2012) showed that drugs affecting the Na+, K+-ATPase/cardiac steroids system are beneficial for the treatment of depression. Hence our work is in accordance to the proposition that mal functioning of the Na+, K+-ATPase/cardiac steroids system may be involved in manifestation of depressive disorders and identify new compounds as potential drug for the treatment of these maladies.

Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function

The classical and best documented effect of cardiac steroids, as their name implies, is to increase the force of contraction of heart muscle. Indeed, cardiac steroids were widely used in Western and Eastern clinical practices for the treatment of heart failure and atrial fibrillation. Despite extensive research, the mechanism underlying cardiac steroids actions have not been fully elucidated. The dogmatic explanation for cardiac steroids-induced increase in heart contractility is that the inhibition of Na+, K+-ATPase by the steroids causes an increase in intracellular Na+ which, in turn, attenuates the Na+/Ca++ exchange, resulting in an increased intracellular Ca++ concentration, and hence greater contractility. However, recent observations led to the hypothesis that the ability of cardiac steroids to modulate a number of intracellular signaling processes may be responsible for both short- and long-term changes in CS action on cardiac function. We are addressing this hypothesis using the zebrafish model and our ability to quantify heart function in-vivo. Heart contractility measurements were performed using a series of software tools for the analysis of high-speed video microscopic images, allowing the determination of ventricular heart diameter and perimeter during both diastole and systole. The ejection fraction (EF) and fractional area changes (FAC) were calculated from these measurements, providing two independent parameters of heart contractility (see attached movie bellow). We are currently testing the effect of cardiac steroids in the presence and absence of intracellular signaling pathways (MAP, AKT, IP3R) inhibitors. Reduction in the steroids ability to increase the force of contraction will serve as the first evidence, in-vivo, for the participation of the signaling processes in the molecular mechanisms responsible for the action of cardiac steroids on heart muscle.

Laboratory Techniques

We employ a broad range of preparations and techniques. These include isolated organs (arterial rings, smooth and cardiac muscle strips) and isolated nerve endings, as well as primary and established tissue-cultured cells. Our studies involve the application of biochemical and immunological techniques (transport and enzymatic activity measurements, RIA, ELISA), molecular biological techniques (e.g., Western and Northern blotting, and PCR), protein purification (HPLC), cellular techniques muscle contractility, cell proliferation and differentiation’ in-vivo measurements of heart contractility and blood flow in Zebrafish and behavior measurements in rodents.

Biography

Education

1970	B.Sc. in Physiology and Zoology, The Hebrew University, Jerusalem, Israel
1970-1972	M.Sc. in Physiology, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
1973-1977	Ph.D., Department of Physiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. (Thesis: “Increased Production of Gamma Aminobutyryl choline in Cerebral Cortex Caused by Afferent Electrical Stimulation” (Thesis Advisors: Prof. J. Dobkin and Prof. J. Magnes).
1977-1979	Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.

Positions held

1970-1972	Teaching and Research Assistant, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1972-1974	Assistant Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1975-1977	Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1977-1979	Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.
1979-1983	Lecturer, (REVSON fellowship) Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1981 (summer)	Visiting Scientist, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, USA
1983-1987	Senior Lecturer, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
1985-1986	Visiting Scientist, Laboratory of Theoretical and Physical Biology, NICHD, National Institutes of Health, Bethesda, Maryland, USA
1988-1994	Associate Professor, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1994-present	Professor of Physiology, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1997-1998	Visiting Scientist, Laboratory of Mechanisms of Ocular Diseases, NEI, National Institutes of Health, Bethesda, Maryland, USA
2007 (summer)	Visiting Professor, Department of Physiology, Pharmacology, Metabolism and cardiovascular Sciences, Medical Center University of Toledo, Toledo, Ohio, USA
2007-2011	Jacob Gitlin Chair in Physiology, The Hebrew University, Jerusalem, Israel
​2011-present	​Walter & Greta Stiel Chair in Heart Studies, The Hebrew University, Jerusalem

Professional Membership

1979-present	International Society of Neurochemistry
1979-present	Israel Society for Physiological and Pharmacological
1980-present	Society of Neurosciences (Europe)
1986-present	The American Society of Hypertension
1992-present	Israeli Society for Neurosciences
1999-present	The American Physiological Society

Editorial Tasks

Serving as a Reviewer for the scientific journals:
•	American Journal of Hypertension		•	Journal of Neural Transmission
•	American Journal of Physiology		•	Journal of Neurochemistry
•	Apoptosis		•	Journal of Pharmacology and Experimental Therapeutics
•	Biochemical and Biophysical Research Communications		•	Life Sciences
•	Basic Journal of Physiology and Pharmacology		•	NANO
•	Brain Research		•	Neurochemistry International
•	Bioconjugate Chemistry		•	Neuroscience
•	Cell Calcium		•	Neurotoxicity Research
•	Clinical Science		•	Pathophysiology
•	Endocrinology		•	Physiology and Behavior
•	European Neuropsychopharmacology		•	PNAS
•	General and Comparative Endocrinology		•	Psychiatry Research
•	Hypertension		•	Translational Research
•	Journal of Cell Sciences

University and Other Activities

1982-1985	Chairman of the Neurobiology Teaching Division, The Hebrew University, Jerusalem
1988-1994	Elected representative of the Senior Lecturers and Associate Professors for the University Senate
1989-1997	Member of the admission committee of the Medical School, The Hebrew University, Jerusalem
1990-1996	Member of the Committee for cellular biology of the graduate studies, The Hebrew University, Jerusalem
1992-1996	Member of the Teaching Committee, Faculty of Medicine, The Hebrew University, Jerusalem
1992-1996	Chairman, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem
1994-1997	Member of the Committee for graduate studies, The Hebrew University, Jerusalem
1992-2002	Member of the Management Committee of The Institute for Medical Sciences, Faculty of Medicine, The Hebrew University, Jerusalem
1996-1999	President of the Israel Society for Physiology and Pharmacology
1998- 2002	Chairman, Institute of Medical Sciences, The Hebrew University, Hadassah Medical School, Jerusalem
1999-2002	Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2007–Present	Elected representative of the Professors for the executive University Senate
2008-2012	Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2008-2012	Chairman, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem
2009 – Present	Elected member of the Senate to the Executive Committee of the Hebrew University

 https://medicine.ekmd.huji.ac.il/En/Publications/ResearchersPages/pages/davidli.aspx

PUBLICATIONS 2006 – 2012

Use link below for earlier publications

https://medicine.ekmd.huji.ac.il/En/Publications/publications/Pages/default.aspx?aut=Lichtstein,%20D

Search By:  Author Abeles, M Abramovitch, R Allweis, C Altuvia, S Amedi, A Amster-Choder, O Anglister, L Aqeilan, RI Aronovitch, Y Bachrach, U Baniyash, M Barak, V Barenholz, Y Bar-Shalita, T Bar-Shavit, R Bar-Shavit, Z Bar-Tana, J Becker, Y Behar, O Ben-Ishay, Z Benita, S Ben-Neriah, Y Benny, O Ben-Or, S Ben-porath, I Ben-Sasson, S Ben-Sasson, SZ Ben-Shaul, Y Ben-Yehuda, S Bercovier, H Berger, M Bergman, H Bergman, Y Berry, E Bialer, M Binshtok, AM Blum, G Brandes, R Brautbar, C Breuer, E Cedar, H Chevion, M Chinitz, D Citri, N Cohen, A Cohen, E Deutsch, J Dikstein, S Domb, A Dor, Y Dror, OE Dzikowski, R Elkin, M Engelberg-Kulka, H Even-Ram, S Eyal, S Fainsod, A Feintuch, U Friedlander, y Friedman, M Gallily, R Gatt, S Gerlitz, O Gertz, SD Gibson, D Glaser, G Goelman, G Goldberg, I Goldberg, JA Goldblum, A Golenser, J Golomb, G Golos, A Gordon, A Gorinstein, S Gorodetsky, R Granot, Z Greenblatt, CL Greenwald, T Gross, E Grover, N Gutman, Y Hahn-Markowitz, J Hamburger, J Hanani, M Hanski, E Hartman-Maeir, A Hellman, A Hochner, H Hoffman, A Honigman, A Horowitz, M Ilani, A Inbal, A Jaffe, CL Jarrous, N Kaempfer, R Kalcheim, C Kanner, BI Kapitulnik, J Karni, R Katz, E Katzav, S Katz-Brull, R Katzhendler, J Kedar, E Keren, N Keshet, E Klar, A Kohen, R Konijn, A Kotler, M Langer, D Laskov, R Lazarovici, P Levi-Schaffer, F Lev-Tov, A Lichtstein, D Liebergall, M Lorberboum-Galski, H Magen, H Mandelboim, O Manor, O Margalit, H Matok, I Mechoulam, R Meiri, H Melloul, D Meyuhas, O Minke, B Mishani, E Mitrani-Rosenbaum, S Mumcuoglu, K Naor, D Naveh-Many, T Neumark, Y Nussinovitch, I Oppenheim, A Ornoy, A Panet, A Paroush, Z Parush, S Peled, A Pikarsky, E Pines, O Priel, A Prut, Y Rachmilewitz, J Rahamimoff, H Ravid, S Razin, A Razin, E Razin, S Reich, R Reshef, L Richter, E Ringel, I Rokem, JS Rom, M Ron, A Rosen, H Rosenshine, I Rotenberg-Shpigelman, S Rotshenker, S Rottem, S Rubinstein, A Samueloff, S Samuni, A Sasson, S Schlein, Y Schlesinger, M Schueler-Furman, O Sharon, D Sharon, R Shaulian, E Shlomai, J Shmueli, A Shohami, E Shtarkshall, R Shurki, A Simon, I Smith, P Sohmer, H Sperling, D Steinitz, M Stern-Bach, Y Tal, M Taraboulos, A Ta-Shma, R Tirosh, B Touitou, E Trachtenberg, S Traub, R Treinin, M Tsvelikhovsky, D Vaadia, E Warburg, A Weinstock, M  Weintraub, N Weiss, D Weiss, R Wiener, R Wormser, U Yaari, Y Yagen, B Yaka, R yanai, J Yavin, E Yedgar, S Yefenof, E Yisraeli, JK Yochman, A Yogev, D Yosselson-Superstine, S Zajicek, G Zakay-Rones, Z  Sort By:  Year Descending Year Ascending  Text: Dvela, M., Rosen, H., Ben-Ami, H. C., Lichtstein, D. Endogenous ouabain regulates cell viability American journal of physiology. Cell physiology, 302(2), C442-52, 2012 JCR Impact FactorAbstract Goldstein, I., Lax, E., Gispan-Herman, I., Ovadia, H., Rosen, H., Yadid, G., Lichtstein, D. Neutralization of endogenous digitalis-like compounds alters catecholamines metabolism in the brain and elicits anti-depressive behavior European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 22(1), 72-9, 2012 JCR Impact FactorAbstract Feldmann, T., Shahar, M., Baba, A., Matsuda, T., Lichtstein, D., Rosen, H. The Na(+)/Ca(2+)-exchanger: an essential component in the mechanism governing cardiac steroid-induced slow Ca(2+) oscillations Cell calcium, 50(5), 424-32, 2011 JCR Impact FactorAbstract Nesher, M., Shpolansky, U., Viola, N., Dvela, M., Buzaglo, N., Cohen Ben-Ami, H., Rosen, H., Lichtstein, D. Ouabain attenuates cardiotoxicity induced by other cardiac steroids British journal of pharmacology, 160(2), 346-54, 2010 JCR Impact FactorAbstract Guttmann-Rubinstein, L., Lichtstein, D., Ilani, A., Gal-Moscovici, A., Scherzer, P., Rubinger, D. Evidence of a parathyroid hormone-independent chronic effect of estrogen on renal phosphate handling and sodium-dependent phosphate cotransporter type IIa expression Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 42(4), 230-6, 2010 JCR Impact FactorAbstract Jaiswal, M. K., Dvela, M., Lichtstein, D., Mallick, B. N. Endogenous ouabain-like compounds in locus coeruleus modulate rapid eye movement sleep in rats Journal of sleep research, 19(1 Pt 2), 183-91, 2010 JCR Impact FactorAbstract Nesher, M., Dvela, M., Igbokwe, V. U., Rosen, H., Lichtstein, D. Physiological roles of endogenous ouabain in normal rats American journal of physiology. Heart and circulatory physiology, 297(6), H2026-34, 2009 JCR Impact FactorAbstract Goldstein, I., Lerer, E., Laiba, E., Mallet, J., Mujaheed, M., Laurent, C., Rosen, H., Ebstein, R. P., Lichtstein, D. Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders Biological psychiatry, 65(11), 985-91, 2009 JCR Impact FactorAbstract Nesher, M., Vachutinsky, Y., Fridkin, G., Schwarz, Y., Sasson, K., Fridkin, M., Shechter, Y., Lichtstein, D. Reversible pegylation prolongs the hypotensive effect of atrial natriuretic peptide Bioconjugate chemistry, 19(1), 342-8, 2008 JCR Impact FactorAbstract Dvela, M., Rosen, H., Feldmann, T., Nesher, M., Lichtstein, D. Diverse biological responses to different cardiotonic steroids Pathophysiology : the official journal of the International Society for Pathophysiology / ISP, 14(3-4), 159-66, 2007 JCR Impact FactorAbstract Feldmann, T., Glukmann, V., Medvenev, E., Shpolansky, U., Galili, D., Lichtstein, D., Rosen, H. Role of endosomal Na+-K+-ATPase and cardiac steroids in the regulation of endocytosis American journal of physiology. Cell physiology, 293(3), C885-96, 2007 JCR Impact FactorAbstract Chirinos, J. A., Corrales-Medina, V. F., Garcia, S., Lichtstein, D. M., Bisno, A. L., Chakko, S. Endocarditis associated with antineutrophil cytoplasmic antibodies: a case report and review of the literature Clinical rheumatology, 26(4), 590-5, 2007 JCR Impact FactorAbstract Nesher, M., Shpolansky, U., Rosen, H., Lichtstein, D. The digitalis-like steroid hormones: new mechanisms of action and biological significance Life sciences, 80(23), 2093-107, 2007 JCR Impact FactorAbstract Lichtstein, D. M., Arteaga, R. B. Rhabdomyolysis associated with hyperthyroidism The American journal of the medical sciences, 332(2), 103-5, 2006 JCR Impact FactorAbstract Morla, D., Alazemi, S., Lichtstein, D. Stauffer’s syndrome variant with cholestatic jaundice: a case report Journal of general internal medicine, 21(7), C11-3, 2006 JCR Impact FactorAbstract Chirinos, J. A., Corrales, V. F., Lichtstein, D. M. ANCA-associated large vessel compromise Clinical rheumatology, 25(1), 111-2, 2006 JCR Impact FactorAbstract Deutsch, J., Jang, H. G., Mansur, N., Ilovich, O., Shpolansky, U., Galili, D., Feldman, T., Rosen, H., Lichtstein, D. 4-(3’alpha15’beta-dihydroxy-5’beta-estran-17’beta-yl)furan-2-methyl alcohol: an anti-digoxin agent with a novel mechanism of action Journal of medicinal chemistry, 49(2), 600-6, 2006 JCR Impact FactorAbstract Goldstein, I., Levy, T., Galili, D., Ovadia, H., Yirmiya, R., Rosen, H., Lichtstein, D. Involvement of Na(+) Biological psychiatry, 60(5), 491-9, 2006 JCR Impact FactorAbstract Chirinos, J. A., Garcia, J., Alcaide, M. L., Toledo, G., Baracco, G. J., Lichtstein, D. M. Septic thrombophlebitis: diagnosis and management American journal of cardiovascular drugs : drugs, devices, and other interventions, 6(1), 9-14, 2006 JCR Impact FactorAbstract Rosen, H., Glukmann, V., Feldmann, T., Fridman, E., Lichtstein, D. Short-term effects of cardiac steroids on intracellular membrane traffic in neuronal NT2 cells Cellular and molecular biology (Noisy-le-Grand, France), 52(8), 78-86, 2006 JCR Impact FactorAbstract

SOURCE

https://medicine.ekmd.huji.ac.il/En/Publications/publications/Pages/default.aspx?aut=Lichtstein,%20D

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading...

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, BioSimilars, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Ionic Transporters Na+, Na-K transport, Origins of Cardiovascular Disease, Pharmacotherapy and Cell Activity, Pharmacotherapy of Cardiovascular Disease, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, Translational Research, Translational Science, Water Transporters | Tagged Hebrew University of Jerusalem, pharmacology, Roche Institute of Molecular Biology | Leave a Comment »

TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

December 18, 2013 by 2012pharmaceutical

TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

Reporter: Aviva Lev-Ari, PhD, RN

A step toward development of drugs for diseases such as Alzheimer’s, Parkinson’s and Huntington’s

December 3, 2013

 

Jerusalem – A successful joint collaboration between researchers at The Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.

Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s andHuntington’s diseases share two key features: they stem from toxic proteinaggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at The Hebrew University of Jerusalem‘s Faculty of Medicine.

Dr. Cohen’s first breakthrough in this area occurred when he discovered, working with worms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.

Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Professor Alexander Levitzki from the Department of Biological Chemistry at The Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.

Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.

The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.

Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of The Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with The Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.

Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.

SOURCE

http://www.afhu.org/step-toward-development-drugs-diseases-such-alzheimers-parkinsons-and-huntingtons

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading...

Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, Etiology, Innovation in Immunology Diagnostics, Innovations in Neurophysiology & Neuropsychology, Pharmacotherapy and Cell Activity | Tagged Alexander Levitzki, Alzheimer, Alzheimers Disease, Hebrew University of Jerusalem, Huntington's disease, neurodegeneration, Rosetrees Trust | Leave a Comment »

« Newer Posts - Older Posts »

• Follow Blog via Email

  Enter your email address to follow this blog and receive notifications of new posts by email.

  Email Address

  Follow

  Join 2,056 other subscribers

• Recent Posts

  • Grok thinks like PhDs – Hybrid Model for Autonomous Update of Doctoral Dissertations with Original PhD Student Author editing and acceptance of Grok’s updated output. 3rd Joint article, a pilot study for Validation of an Autonomous Journal Articles Updating System (AJAUS) tested on Autonomous Update of Aviva Lev-Ari, PhD, RN Doctoral Thesis, UC, Berkeley, 1983. January 31, 2026
  • 2026 World Economic Forum, 1/19 – 1/23/2026, Davos, Switzerland, LPBI Group’s KOLs interpretation of AI in Health Videos January 24, 2026
  • Evolving LPBI Group’s Portfolio of Intellectual Properties (IP): From 2021 Vision to 2026 Reality January 12, 2026
  • Aviva Lev-Ari, PhD, RN – Biography ->> Grokepedia Entry January 11, 2026
  • List of Articles included in the Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter January 10, 2026
  • Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter January 10, 2026
  • Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com January 10, 2026
  • The youngest leader in AI in Health: Tanishq Mathew Abraham, Ph.D. (@iScienceLuvr) January 8, 2026
  • 2026 Grok Multimodal Causal Reasoning on Proprietary Cariovascular Corpus: From 2021 Wolfram NLP Baseline to Thousands of Novel Relationships – A Second Head-to-Head Validation of LPBI’s Domain-Aware Training Advantage January 6, 2026
  • Workflow for Dynamic Linkage and Transition between two Authoring Systems: LPBI Group’s WordPress.com Multi-Authors Authoring System and Microsoft PowerPoint product for Slide show presentation – Part 10.1 in Composition of Methods January 6, 2026

• Archives

  Archives Select Month January 2026  (10) December 2025  (8) November 2025  (8) October 2025  (12) September 2025  (2) July 2025  (4) June 2025  (8) May 2025  (4) April 2025  (2) March 2025  (1) February 2025  (2) January 2025  (3) December 2024  (1) November 2024  (5) October 2024  (7) September 2024  (7) August 2024  (1) June 2024  (1) May 2024  (2) April 2024  (2) January 2024  (1) November 2023  (1) October 2023  (3) September 2023  (3) August 2023  (2) July 2023  (2) June 2023  (7) May 2023  (4) April 2023  (2) March 2023  (5) February 2023  (2) January 2023  (3) December 2022  (2) October 2022  (6) September 2022  (2) August 2022  (1) July 2022  (3) June 2022  (3) May 2022  (8) April 2022  (10) March 2022  (7) February 2022  (7) January 2022  (3) December 2021  (3) November 2021  (4) October 2021  (11) September 2021  (5) August 2021  (8) July 2021  (21) June 2021  (8) May 2021  (10) April 2021  (8) March 2021  (15) February 2021  (17) January 2021  (20) December 2020  (10) November 2020  (12) October 2020  (26) September 2020  (17) August 2020  (22) July 2020  (27) June 2020  (33) May 2020  (26) April 2020  (42) March 2020  (22) February 2020  (11) January 2020  (7) December 2019  (20) November 2019  (13) October 2019  (11) September 2019  (3) August 2019  (8) July 2019  (25) June 2019  (47) May 2019  (40) April 2019  (27) March 2019  (29) February 2019  (17) January 2019  (50) December 2018  (14) November 2018  (17) October 2018  (18) September 2018  (17) August 2018  (8) July 2018  (20) June 2018  (22) May 2018  (17) April 2018  (12) March 2018  (20) February 2018  (26) January 2018  (16) December 2017  (6) November 2017  (20) October 2017  (13) September 2017  (16) August 2017  (16) July 2017  (19) June 2017  (20) May 2017  (32) April 2017  (21) March 2017  (10) February 2017  (24) January 2017  (21) December 2016  (43) November 2016  (8) October 2016  (40) September 2016  (67) August 2016  (59) July 2016  (75) June 2016  (37) May 2016  (95) April 2016  (152) March 2016  (175) February 2016  (196) January 2016  (139) December 2015  (90) November 2015  (287) October 2015  (237) September 2015  (115) August 2015  (96) July 2015  (63) June 2015  (44) May 2015  (53) April 2015  (76) March 2015  (95) February 2015  (83) January 2015  (75) December 2014  (75) November 2014  (88) October 2014  (135) September 2014  (117) August 2014  (88) July 2014  (88) June 2014  (109) May 2014  (60) April 2014  (85) March 2014  (58) February 2014  (72) January 2014  (107) December 2013  (104) November 2013  (136) October 2013  (62) September 2013  (32) August 2013  (46) July 2013  (74) June 2013  (110) May 2013  (112) April 2013  (86) March 2013  (92) February 2013  (63) January 2013  (63) December 2012  (46) November 2012  (71) October 2012  (84) September 2012  (82) August 2012  (122) July 2012  (59) June 2012  (34) May 2012  (46) April 2012  (2)

• Categories

  Categories Select Category 3D Printing for Medical Application  (239)    3D Plotting Scaffolds  (44)    BioInks  (34)       Biopolymer Blend Open Porous  (18)       Dental Applications  (10)    BioPrinting in Regenerative Medicine  (77)       Cell Level  (16)       MicroEngineering Cell-Tissue & Systems  (31)       Tissue Engineering  (37)    Cardiovascular and Vascular Systems  (30)       Artificial Vascular Structures  (9)       Cardiovascular Tissue  (8)    Drug Development using MultiOrgan Chip  (11)    Drug Development/Formulation using 3D Printing  (10)    MEMS  (16)       Bio-MEMS  (12)    Organ-on-a-Chip  (11)    Programmable Sensors (Carbon Nano Tubes)  (5) 3rd Party IP: Drug DIscovery  (1) 4D Printing and Meta Materials  (10) Academic Publishing  (223)    Key Opinion Leaders in eScientific Publishing – Interviews with  (8) Advanced Drug Manufacturing Technology  (96)    Antimalarial Preparation  (8)    Autologous Cell Therapy  (14)    Automated Cell Processing  (13) Allergy and Infectious Diseases  (12) Alzheimer’s Disease  (163)    Etiology  (77)    Medical Device Therapies for Altzheimer’s Disease  (15)    Pharmacotherapy and Cell Activity  (51) Anticancer Resistance  (31) Art Exhibits on the Human Condition  (1) Art Inspires Science  (4) Article Type  (2)    Authored  (1)    Curated  (2)    Scientific report  (1) Artificial Heart  (2) Artificial Intelligence – General  (232)    An executive’s guide to AI  (10)    Artificial Intelligence – Breakthroughs in Theories and Technologies  (115)    Artificial Intelligence Applications in Health Care  (125)       Artificial Intelligence in CANCER  (39)       Artificial Intelligence in Health Care – Tools & Innovations  (74)    Artificial Intelligence in Medicine – Application for Diagnosis  (69)       Artificial intelligence applications for cardiology  (31)          AI-assisted Cardiac MRI  (10)       Artificial Intelligence in Psychiatry  (6)       Deep Learning in Pathology  (18)    Artificial Intelligence in Medicine – Applications in Therapeutics  (64)    ChatGPT, GPT-4  (7)       ChatGPT at LPBI Group  (3)       ChatGPT in Academic Education  (3)    Machine Learning  (71)       Deep Learning  (25)       Natural Language Processing (NLP)  (45)    Machine learning in predicting type 2 diabetes  (5) Auditory and vision  (13) Autism Spectrum Disorders  (10) Autoimmune Inflammatory DIseases  (24)    Crohn’s disease  (5)    Tolerance-inducing Autoimmune Disease Therapeutics  (6)    Ulcerative Colitis  (3) Autophagosome  (4) Bacterial Resistance  (25) Behavior  (26) Behavioral Genetics  (21) Big Data  (88)    Intelligent Information Systems  (51) Bio Instrumentation in Experimental Life Sciences Research  (368)    Analytical Instruments Industry  (5)    Microfuidics  (8) Bio-Ethics  (15) BioBanking  (36) Biodegradable Drug-eluting Material  (8) Bioengineering & reverse engineering design  (43) BioIT: BioInformatics  (147) BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics  (135)    Advanced Computing Platform  (32)       Blockchain Transactions System  (6)          Platform for Content Monetization embedded Content Promotion  (1)    Pancreatic adenocarcinoma classifier  (4)    Simulation Modeling in NGS  (5) Biological Engineering  (43) Biological Networks  (193) Biological Networks, Gene Regulation and Evolution  (479)    Virology  (10) Biomarkers & Medical Diagnostics  (571)    VOC – Volatile Organic Compounds as BioMarkers  (2) Biomedical Measurement Science  (173) BioSimilars  (112) BioTechnology – Venture Creation  (131)    Foundations for supporting Science and Education  (14)    Philanthropy to Academic Institution  (3) BioTechnology – Venture Creation, Venture Capital  (108)    Seeking Talent  (3) BiVAD  (1) Blindness  (6) Bone Disease and Musculoskeletal Disease  (82) Brain Basis of Emotion  (5) Business Career Consideration  (1) Ca2+ triggered activation  (61) Calcium  (21) Calcium Signaling  (71) Calmodulin Kinase and Contraction  (36) Cancer – General  (186) Cancer and Current Therapeutics  (411)    interventional oncology  (49)       Breast Cancer – impalpable breast lesions  (20)       Prostate Cancer: Monitoring vs Treatment  (9) CANCER BIOLOGY & Innovations in Cancer Therapy  (1,122)    Anaerobic Glycolysis  (51)    Cachexia  (18)    Cancer Genomics  (84)       Circulating Tumor Cells (CTC)  (27)          Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood  (17)             mRNA  (6)          MagSifter chip  (1)       KRAS Mutation  (9)       Li-fraumeni syndrome.  (3)       TP53 – Germline mutations  (8)    cancer metabolism  (28)    Funding Opportunities for Cancer Research  (12)    Genomic Expression  (150)    Glioblastoma  (7)    Hexokinase  (14)    Loss of function gene  (18)    Metabolic Immuno-Oncology  (21)    Metastasis Process  (15)    Methylation  (33)    Microbiome and Responses to Cancer Therapy  (10)    Monoclonal Immunotherapy  (29)    mtDNA  (13)    Oxidative phosphorylation  (56)    Pancreatic cancer  (10)    Pyruvate Kinase  (27)    The NCI Formulary  (1)    tumor microenvironment  (16)    Warburg effect  (50) Cancer Informatics  (104) Cancer Prevention: Research & Programs  (131) Cancer Screening  (108) Cancer Vaccines: Targeting Cancer Genes for Immunotherapy  (30)    Engineering Enhanced Cancer Vaccines  (3) cancer-general  (6) Cardiac and Cardiovascular Surgical Procedures  (328)    Aortic Valve: TAVR, TAVI vs Open Heart Surgery  (91)       Prosthesis-Patient Mismatch (PPM) in TAVI vs SAVR  (2)       TAVI vs Open Heart Surgery  (6)       Transcatheter Aortic Valve Replacement via the Transcarotid Access  (3)       Transcaval TAVR Procedure  (3)       Valve-in-Valve Procedure  (5)    Atrial Fibrilation (a-Fib), Cardiac Pacing and Arrhythmias  (18)    BackBeat’s Cardiac Neuromodulation Therapy (CNT) bioelectronic therapy  (1)    CABG  (47)    Cancer Surgery of the Heart  (10)    Cardiovascular Fluid Management: algorithms  (1)    Heart Transplant  (16)    Heart-Lung Transplant  (11)    Implantation  (3)    Left Main Coronary Artery Disease (LMCAD)  (3)    Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart  (22)    Mitral Valve: Repair and Replacement  (64)       TMVR – Transcatheter Mitral Valve Repair  (5)    PCI  (108)       Bioresorbable Vascular Scaffold (BVS)  (4)       Invasive FFR for PCI  (2)       Multivessel PCI FFR Guidance  (1)       Robotic-assisted percutaneous coronary intervention  (2)       Stent Retriever in endovascular thrombectomy  (3)    Peripheral Arterial Disease & Peripheral Vascular Surgery  (65)       Abdominal Aorta  (20)       Carotid Artery  (15)       Limb ischemia  (4)       Thoracic Aorta  (16)    Pulmonary Valve Replacement and Repair  (3)    Renal Denervation  (20)    Replacement  (1)    Robotically assisted Cardiothoracic Surgery  (2)    Tricuspid Valve Repair  (7)    Vena Caval Filters: Device for Prevention of Pulmonary Embolism and Thrombosis  (2) Cardiovascular Pharmacogenomics  (171) Cargo  (3) Cell Biology  (323) Cell Biology, Signaling & Cell Circuits  (672)    Apoptosis  (17)    Autophagy-Modulating Proteins  (6)    “Antibody–enzyme conjugates”  (6)    Cell Processing System in Cell Therapy Process Development  (27)    Endoplasmic reticulum  (3)    Enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)  (3)    Ubiquitin  (11) Cerebrovascular and Neurodegenerative Diseases  (123)    Stroke  (9) Chemical Biology and its relations to Metabolic Disease  (464)    #BIGAxisSummit  (1)    Gut Microbiome and Obesity  (8) Chemical Genetics  (350) Child and Adolescent Psychiatry  (13) Childhood cancer  (17) Childhood malnutrition  (3) children  (3) Circulating Progenitor Cells  (27)    Bone marrow derived cells  (17)    Endothelial cells  (7)    Umbilical cord cells  (6) Clinical & Translational  (238) Clinical Diagnostics  (220)    Mass automation of plasma proteins  (13) Clinical Genomics  (144) Coagulation Therapy and Internal Bleeding  (83) Cognition  (47) Commercialization  (20) Components and IRB related issues  (4) Computational Biology/Systems and Bioinformatics  (470)    Computational Histopathology  (3)    Meta-analysis of transcriptome data  (10) Conference Coverage with Social Media  (494)    MassBio  (3) coronavirus  (18) COVID-19  (20) CRISPR/Cas9 & Gene Editing  (192)    CRISPR alternative for editing genes without cutting  (14)       CAST – Alternative to CRISPR/Cas9  (3)       Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration  (4)    CRISPR applied to Human Germ Line  (13)       Gene Editing Impact on Longevity  (6) CT  (20) Cytokines  (20) Cytoskeleton  (85) Developmental biology  (107) Diabetes Mellitus  (146)    Artificial Pancreas for Type 2 Diabetes  (4)    Artificial Pancreas for Type1 Diabetes  (8)    Gestational diabetes  (5) Diagnostic Immunology  (61) Diagnostics and Lab Tests  (128)    Liquid Biopsy: Circulating Tumor Cells in Urine and Blood  (9) Digital HealthCare – biotech & internet joint ventures  (47) Disease Biology  (334) Disease Biology, Small Molecules in Development of Therapeutic Drugs  (487) DNA repair  (73)    Apoptosis  (13)    Autophagy  (13)    Cell death pathways  (19)    Proteolysis  (8)    Proteosome  (8) Drug Delivery Platform Technology  (157)    Drug Carrier Design  (21)       Medication Remote Compliance Monitoring  (3)    Exosomes: Natural Carriers for siRNA Delivery  (9) Drug Toxicity  (74) Ecosystems & Industrial Concentration in the Medical Device Sector  (172)    Cardiac & Vascular Repair Tools Subsegment  (128)    Exec Compensation in the Cardiac & Vascular Repair Tools Subsegment  (14)    Massachusetts Niche Suppliers and National Leaders  (20) Electronic Health Record  (10) Embryology  (24) Empathy  (6) Endocrine Diseases  (60) Enzyme Induction  (46)    ion-transporting enzyme  (2)    K + -ATPase.  (1)    Na +  (2) Epigenetics and Environmental Factors  (35) Ethics and Leadership  (10) Executive Compensation – Big Pharma  (3) Fat soluble vitamins  (4) FDA  (71) FDA Regulatory Affairs  (358)    FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP, GLP, ISO 14155  (52)    ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics  (30) Fetal Ultrasound  (2) Fiction and medicine  (5) Frontiers in Cardiology and Cardiovascular Disorders  (929)    Acute Myocardial Infarction  (63)       Cardiogenic Shock  (5)    Anemia in CVD Patients  (6)    Cardio-Oncology  (4)    Cardiomyopathy  (57)    Cardiovascular Research  (187)       Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism  (64)       Pre-Clinical Animal Model Development  (23)    Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH)  (20)    Cost of Inpatient Stay for Cardiovascular Diagnosis for Admission  (1)    Electrophysiology  (111)       Ablation Procedure vs Drug Therapy  (2)       Arrhythmia Detection with Machine Learning Algorithms  (7)       Cardiotoxic Risks of Immune Checkpoint Inhibitors  (1)       Genomic Analysis of EKG Electrophysiology Genomics  (3)       implantable cardioverter defibrillator (ICD) and External Defibrillation  (1)       implantable pacemaker  (2)       Rare heart rhythm disorders and Long QT syndrome (LQTS)  (7)    Epigenetics and Cardiovascular Risks  (57)    Heart Failure (HF)  (51)       Acute coronary syndrome  (7)       congestive heart failure  (19)       Hypertensive Disorders of Pregnancy  (1)    Medical Devices R&D and Inventions  (212)       Assist Devices: LV  (3)       RV  (1)       Stents & Tools  (90)       Valves & Tools  (67)    Origins of Cardiovascular Disease  (422)       Atherogenic Processes & Pathology  (180)       Congenital Heart Disease  (34)          Genetic Mutations in Congenital Heart Disease  (4)       inflammation independent of lipid levels  (13)       Systemic Inflammatory Diseases as CVD Risk  (12)    Pharmacotherapy of Cardiovascular Disease  (356)       HTN  (176)       HTN in Youth  (8)       Resident-cell-based  (43)       Subarachnoid Hemorrhage (SAH)  (1)       Transthyretin amyloid cardiomyopathy (ATTR-CM)  (1)    Spontaneous Coronary Artery Dissection (SCAD)  (6)    Stroke  (15)       endovascular thrombectomy  (6)    Vascular Diseases  (21)       mesenteric ischemia  (3) Future Pandemics Inform-graphics  (1) Gastroenterology  (38) Gene Regulation  (232) Gene Regulation and Evolution  (137) Genetics & Innovations in Treatment  (176) Genetics & Pharmaceutical  (203) Genome Biology  (967)    Exosomes  (25)    Gene Therapy & Gene Editing Development  (42)    mRNA Therapeutics  (20)    Mutagenesis  (27)    Single Cell Genomics  (25)    Single-cell sequencing  (20)    Variation in human protein-coding regions  (35) Genomic Endocrinology  (42) Genomic Testing: Methodology for Diagnosis  (416) Genomics Pharmacy  (40) Global Market of Medical Devices Technology  (2) Global Medical Publishers by Country  (3) Global Partnering & Biotech Investment  (47) GLP  (4) Glycobiology: Biopharmaceutical Production  (16) Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics  (28) Health Care System by Country  (58)    AI Models in Healthcare  (12)    Centers for Medicare & Medicaid Services  (8)    Health in Israel  (2)    India  (1)    United States  (27)       Hospital-based Medical Innovations  (10)       Medical Recertification and Maintenance of Certification (MOC)  (1) Health Economics and Outcomes Research  (384)    Women Health  (18)       Heart and Brain Disease in Women  (3) Health Law & Patient Safety  (165)    and Bioethics  (14)    Biotechnology  (12)    Health Law Policy  (13) HealthCare IT  (138) Healthcare Reform  (117)    Accountable Care Organizations  (26)    Affordable Care Act  (29)       Repair  (1)       Repeal ACA  (1)       Replace  (1)    Federal Budget Appropriations  (26)    Healthcare costs and reimbursement  (59)    Indigent Nutrition  (14)    Medicare and Medicaid  (20)    Prescription Drugs Costs  (21)    Skilled Nursing Facilities  (6)    Technology Capital Expenses  (15)    Uninsured and Underinsured  (20) Hematology  (100)    Acute lymphocytic leukemia  (18)    Acute myelocytic leukemia  (21)    Hematopoiesis  (48)    Lymphoma  (21) History and physical exam  (6) Human aging  (27) Human Immune System in Health and in Disease  (246) Human Sensation and Cellular Transduction: Physiology and Therapeutics  (21) Image Processing/Computing  (41) Imaging-based Cancer Patient Management  (116) Immuno-Oncology & Genomics  (133)    mRNA platform in Drug DIscovery  (6) Immunodiagnostics  (139)    Cancer-Immune Interactions  (29)    CNS-Immune Interface  (5)    Neuronal Circuits  (4) Immunology  (123)    Adaptive Immune Response to Biomaterials and Tissue Repair  (13)    Antibody Responses Predict Antigen Exposure  (17)    Cytokine Receptor Structure  (8)    Human Antibody Response  (18)    Human Circulating Antibody Repertoire  (11)    Human Naive B Cell Repertoire  (8)    MHC Repertoires for Antigen Prediction  (8)    Protection Against Autoimmune Disease  (11)    Synthetic Immunology: Hacking Immune Cells  (15) Immunotherapy  (133)    CAR-T  (14)    combination immunotherapies.  (14)    Efficacy of Anti-Tumor T Cells  (13)    Engineering Better T Cells  (8)    Immune Engineering  (17)    Immune Modulatory  (15)    Integrin-targeted Combination Immunotherapy  (6)    Modulating Macrophages in Cancer Immunotherapy  (16)    NK Cell-Based Cancer Immunotherapy  (19)    Synergistic Innate and Adaptive Immunotherapy  (14) Income Disparity  (2) Infectious Disease & New Antibiotic Targets  (162)    Antibiotic resistance  (7)    Viral diseases  (37)       Myocarditis  (1) Infectious Disease Immunodiagnostics  (58)    Virology – Vector-borne DIsease  (17) Inflammasome  (29)    Anti-tumor necrosis factor drugs (TNF inhibitors)  (3) Innovation in Immunology Diagnostics  (111)    Universal Immune Cell Therapies (uICT)  (11) Innovations  (186)    R&D Expenditure  (8) Innovations in Neurophysiology & Neuropsychology  (145)    Age and Life Expectancy  (3)    autism spectrum disorder  (1)    Circadian Rhythm and Sleep  (6)    hNPCs  (1)    Nervous System Function  (2)    Relapsing Multiple Sclerosis  (1) Intellectual Property  (83)    Disputes and Settlements  (9)    IP Valuation Models – Pricing Intangible Assets  (7)    Patent Law in Biotech  (12) Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough  (119) International Global Work in Pharmaceutical  (190) Interventional Oncology: Radiofrequency Ablation, Transarterial Chemoembolization, Microwave Ablation and Irreversible Electroporation (IRE)  (12) Interviews with Scientific Leaders  (315)    Albany Medical Center Prize in Medicine and Biomedical Research  (2)    Annual Breakthrough Prize  (4)    Annual Lewis S. Rosenstiel Award  (2)    Awards in Cardiology and Cardiovascular Medicine  (6)    CEOs of Biotech Companies  (3)    Gerald D Aurbach Award for Outstanding Translational Research  (2)    Interviews with Key Opinion Leaders (KOLs)  (10)    James Prize in Science and Technology Integration  (2)    Jessie Stevenson Kovalenko Medal – Medical Sciences  (2)    Lemelson-MIT Prize  (2)    Life Sciences Breakthrough Prize  (5)    Mosteller Statistician of the Year Award  (2)    Mourning the Loss of a Scientific Leader  (3)    National Academy of Sciences AWARDS  (4)    Nobel Prize Winners  (29)    Noble Prize (Not Nobel Prize)  (2)    Paul Marks Prize for Cancer Research  (2)    Russ Prize recognizes bioengineering achievements worldwide  (2)    The Dan David Prize  (6)    Warren Alpert Foundation Prize Recipients  (4)    Wolf Prize  (2)    Wolf Prize in Medicine  (2)    women in science  (5) Investment in Technological Breakthrough  (60) Ionic Transporters Na+  (25) IP Development by LPBI Group Team  (14) IP Development by LPBI Group Team & Other Organizations  (8) ISO 14155  (3) Joint Venture – SBH & M3DP: SOP and Arrangements  (1) Justice & Law  (1) K  (15) Lab-on-a-chip  (2) Landscape  (1) Lasers and photonics  (18)    Midrange IR spectroscopy  (1) Law and Medicine Conflicts  (14) Leadership, Power, Social Interlocking Connections  (13) Lipid metabolism  (109)    Fatty acids  (38)    Lipids  (38)    PCSK9 Inhibitor Therapy  (19) Lipidomics  (11) Liposome  (4) Liver & Digestive Diseases Research  (122) LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management  (143)    Award Nominations  (5)    BioMed e-Books e-Series by LPBI Group  (9)    Feedback from Investors: LPBI Portfolio of Five Businesses  (2)    LPBI Group Founder – Aviva Lev-Ari  (27)    PhD  (1)    RN  (1) LPBI Management  (23) Massachusetts Academy of Sciences (MAS)    (2) Materials Science & Engineering  (37)    Organic BioElectronics  (2) Math  (13)    Great Discoveries  (7) Mechanical Assist Devices: LVAD  (4) Medical and Population Genetics  (193) Medical Devices R&D Investment  (242)    21st Century Cures Act  (2)    CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP  (14)    Rhythm management device hardware: dual-chamber pacemakers  (1)       Systolic HTN  (1) Medical Imaging Technology  (59) Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound  (164)    Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI)  (3)    Echocardiography  (3)    MRI  (18)    Noninvasive Diagnostic Fractional Flow Reserve (FFR) CT  (6)    Ultra Sound  (10) Melatonin & Circadian Regulation  (9) memory loss  (1) Metabolism  (239)    Biochemical pathways  (144)       Enzymes and isoenzymes  (73)          Dehydrogenase  (16)          Kinase  (28)          Phosphatase  (9)          Phosphorylase  (22)          tyrosine decarboxylases  (3)    Inosine nucleotides  (9)    Leloir pathway  (6)    microbiome  (7)    Pentose monophosphate shunt  (14)    Pyridine nucleotides  (28)       Pyridine nucleotide transhydrogenase  (7) Metabolomics  (321) Methods  (37) Mg++  (10) Microbiologial genetics  (36) Microbiology  (68)    Virology  (14) Micronutrients  (16) Microvesicle  (7) Microwave Ablation and Irreversible Electroporation (IRE)  (1) Mobile Healthcare  (5) Molecular Genetics & Pharmaceutical  (377)    Organoids  (3) Monoclonal antibody therapy  (14) Mutant Gene Expression  (42) Myocardial adenine nucleotide metabolism  (6) Myocardial Ischemia  (26) Myocardial Metabolism  (36) Na-K transport  (40) Na-K-ATPase  (27) Nanotechnology for Drug Delivery  (99) Nephrology  (46) Nephrology & Regenerative medicine  (9) Neurodegenerative Diseases  (89)    hNPCs  (3)    MS  (5) Neurohumoral Transmission  (68)    Ca2+ triggered activation  (21)    Calmodulin  (13)    Parkinson’s disease dyskinesia levodopa  (3)    PKC  (13)    Synaptic vesicle  (20) Neurological Diseases  (121) Neuroscience  (126) Next Generation Sequencing (NGS)  (27)    Nanopore sequencing  (1) NIH Common Fund  (1) Nitric Oxide in Health and Disease  (136) Nuclear Medicine  (11) Nutrigenomics  (68) Nutrition  (195)    Nutritional Supplements: Atherogenesis, lipid metabolism  (50) Nutrition and Phytochemistry  (62)    Minerals in Medicine  (4)    Plant extract  (22) Nutrition Disorders  (31) Nutritional Supplements: Atherogenesis  (31) Obesity  (19) Oligonucleotide Therapeutics & Delivery  (7) Oncolytic virus & OncoViro-Therapy  (22)    Synthetic Virology  (1) Organ-on-a-Chip & 3D Printing in Life Sciences  (7) Pain: Etiology, Genetics & Innovations in Treatment  (24) Parasitology  (5)    Malaria  (4)    Tropical diseases  (1) Patents  (34) Patient Experience  (66)    Art therapy  (1)    Hospital reputation  (7)    Humor  (1)    Music therapy  (2)    Pain Alleviation  (7)    Patient Outlook  (28)    Reputation of Interventionist  (4)    Support Staff  (13)    Supportive therapies  (6)       laughfter  (1)    Surgical Procedure  (9) Patient Experience: Personal Memories of Invasive Medical Intervantion  (30) Patient’s Voice: Personal Experience with Invasive Medical Procedures  (18) Perioperative Statins at Noncardiac Surgery  (2) Personal Health Applications: Tech Innovations serves HealhCare  (43) Personalized and Precision Medicine & Genomic Research  (736)    Longevity  (3)    New Drug Approval  (5)    Patient-centered Medicine  (39)       cell-based therapy  (9)       stem cell biology and patient-specific  (7)    Personalized Medicine Coalition  (10)    Precision Cancer Medicine  (31) Phagophore  (2) Pharmaceutical Analytics  (261)    Pharmacologic toxicities  (62) Pharmaceutical Discovery  (109)    Rapid automation of plasma protein pools  (17) Pharmaceutical Drug Discovery  (200)    Drug Development Process  (55)       Drug Discovery Chemistry  (29)    drug repurposing  (10) Pharmaceutical Industry Competitive Intelligence  (343)    Pharmacovigilance  (7)    Value-based Drug Pricing  (8) Pharmaceutical R&D Informatics  (44) Pharmaceutical R&D Investment  (299) Pharmacodynamics and Pharmacokinetics  (24) Pharmacogenomics  (159) Photography Collection  (1) Physics  (12) Placenta  (7) Population genetics  (27) Population Health Management  (204)    Evolution of Biology Through Culture  (14)    U.S. Employment-to-Population Ratio  (8) Population Health Management, Genetics & Pharmaceutical  (643)    COVID-19  (157)       Biomarkers: Inflammation  (37)       Cancer Researchers Fighting COVID-19  (14)       COVID-19 effects on Human Heart  (15)       COVID-19: Pandemic Surgery Guidance  (19)       Economic Impact of Coronavirus Pandemic  (41)       number of asymptomatic infections  (27)       Treatment Protocols for COVID-19  (62)    SARS-CoV-2  (141)       Coronavirus Gene Expression  (66)          SARS-CoV-2 circulating variants   (14)          SARS-CoV-2 Viral Variants  (19)       Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis  (2)       Immune-Mediation (independent immunopathology: lung and reticuloendothelial system)  (30)       Mechanisms of infection by SARS-CoV-2  (21)       SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus  (35)          SARS-COV2 Hijacking the Complement and Coagulation Systems  (19)       Seasonality & Environmental Factors in Resurgence  (26)       Serology tests for coronavirus antibodies  (44)       T-cell response to SARS-CoV-2 infection  (14)       Vaccinology  (51)          Mechanism of Thrombosis with AZ & J&J COVID-19 Vaccines  (5)       Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins  (8)    Virus Infective Acute Respiratory Syndrome: SARS-CoV  (92) Population Health Management, Nutrition and Phytochemistry  (162) Preimplantation Genetic Diagnosis and Reproductive Genomics  (13) Protein-energy malnutrition  (12) Proteomics  (367)    Amino acids  (54)    Proteins  (138) Pulmonary diseases  (16)    Lung and pulmonology  (15) Pulmonary pathology  (8) Radio Frequency (RF)-based Surgical Solutions  (2) REAL TIME Conference Coverage Twitter’s Hashtags and Handles per Presentation/session  (50) Regenerative Biology and Medicine  (92) Regulated Clinical Trials: Design, Methods, Components and IRB related issues  (265) Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics  (113) Reproductive Biology & Bio Instrumentation  (78) RNA Biology  (81)    RNA interference (RNAi) therapeutic  (4) RNA Biology, Cancer and Therapeutics  (64) RVAD  (1) SBIR, SBA, NIH, NSF  (3) Schizophrenia  (16) Scientific & Biotech Conferences: Press Coverage  (182) Scientific Publishing  (609)    Curation  (585)       Curation methodology  (40)       De novo synthesis  (16)       Dialectic  (17)       Discovery process  (72)       Evolutionary cognition  (52)       Experimental validation  (91)       Explanatory  (91)       Historical relevance  (71)       Technology Advance Assessment of  (69)       Theoretic convergence  (27)    Open Access Journals  (37) Scientist: Career considerations  (197)    Big Data & Analytics  (17)    Data Science  (13)    Women in Life Sciences  (12) Scoop.it  (19) Sensors & Analytics  (18) Sepsis  (2) Severe Autism  (3) Signaling  (102)    Phosphorylation  (43)    S-nitrosylation  (13)    Ubiquitinylation  (34) Signaling & Cell Circuits  (130) single cell sequencing  (3) Small Molecules in Development of Therapeutic Drugs  (71) Social Development  (15) Specialized 3D BioPrinters (Cornea  (1) Statistical Methods for Research Evaluation  (137) Stem Cells for Regenerative Medicine  (177)    Cardiac muscle regeneration  (19)    Competition in regenerative stem cell science  (18)    Human neural progenitor cells  (8)    Skeletal muscle regeneration  (9) STORM  (2) Stress Disorders  (19) Substance Abuse  (4) Systemic Inflammatory Response Related Disorders  (161)    Inflammatory Pathophysiology  (9) Technology Transfer: Biotech and Pharmaceutical  (354) therapeutics  (3) Tissue Engineering and Regenerative Medicine  (22) Tissue Microenvironment  (5) Transarterial Chemoembolization  (2) Transcriptomics  (47) Transformative Technologies in Healthcare  (23) Translational Science  (230)    Best evidence  (52)    Bias measurement tools  (2)    Evidence-based decision-making  (29)    Inferential analysis  (25)    Intra-rater error  (1)    Quality Assurance  (8)    Random Error  (2)    Systematic Error (Bias)  (6)    Total error  (2)    Translational Effectiveness  (49)    Translational Research  (92) Trends in Global Economy  (6) Uncategorized  (1,019) Unfolded Protein Response (UPR)  (6) US and Global Economy: Trends and Findings  (9) Venture Capital  (47)    Income Geographic Distribution  (3)    Institutional Capital Raised by Female Founders  (6) virology  (10) Vision  (7) Voices of Patients and Healthcare Providers  (22) Water Transporters  (8) Wearable Tech + Digital Health  (5) Anemia  (22) Neutropenia  (8) Neutrophilia  (9) Platelet count disorder  (9) Folate and B12  (7) Iron deficiency  (5) Myelodysplasia  (13) Myelofibrosis  (10)

• Meta

  • Log in
  • Entries feed
  • Comments feed
  • WordPress.org

• • 2012pharmaceutical
  • sjwilliamspa