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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged bioengineering, Cardiovascular Disorders, computational biology, Coronary artery disease, DNA Sequencing, functional proteomics, gene expression, gene silencing, genetic engineering, Heart Failure, Human Genome Project, Hypertension, MicroRNA, mtRNA, myocardial infarction, nitric oxide, Nitric oxide synthase, Personalized medicine, protein modifications, Proteomics, reverse engineering, RNA, signaling pathways, Stem cell, synbiology on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Article ID #135: Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1. Published on 4/28/2014

WordCloud Image Produced by Adam Tubman

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

• Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
• Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
• Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
• Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
• Enable the discovery of new drugs in the continuing emergence of drug resistance.
• Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

http://synthetic_biology/Introduction_to_Synthetic_Biology_and_Metabolic_Engineering/Kristala_ L.J._Prather/E2/iBiology.htm#/sthash.71kZ0ofr.dpuf

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at

http://science360.gov/obj/video/753bb4fa-aafb-4315-848e-51066ed9799a/finding-way-kristala-l-jones-prather-phd 

Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

David Bartel: micro-RNAs

 

I. Introduction to microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=dupzE66J8u4#t=0

– See more at: http://www.ibiology.org/ibioseminars/genetics-gene-regulation/david-bartel-part-1.html#sthash.nGGr1tIt.dpuf

II. Regulatory Effects of Mammalian microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ#t=0

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240

1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.

In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

• In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
• Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Posted in Acute Myocardial Infarction, Biological Networks, Gene Regulation and Evolution, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, De novo synthesis, Diabetes Mellitus, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Endothelial cells, Epigenetics and Cardiovascular Risks, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical Devices R&D and Inventions, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged Absorb™ Bioresorbable Vascular Scaffold, Acute coronary syndrome, Acute decompensated heart failure, Angioplasty, Array-comparative genomic hybridization, Ca2+/calmodulin-dependent protein kinase, Cardiac & Vascular Repair, cardiac arrhythmias, cardiac biomarkers, cardiac myocyte regeneration, cardiomyocyte transformation, cardiovascular complications, Cardiovascular Risk Reduction, cEPC as Biomarker, Circulating Progenitor Endothelial Cells, comparative genomic hybridization, complement activation, endothelial cell, Endothelial Cell Coagulation Activation, functional genomics, Genome Biology, Genome engineering, Human Umbilical Vein Endothelial Cells (HUVECS), Induced pluripotent stem cells (iPS), regenerative medicine, Therapeutic Potential of cEPCs on April 27, 2014| Leave a Comment »

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This document is entirely devoted to medical and surgical therapies that have made huge strides in

• simplification of interventional procedures,
• reduced complexity, resulting in procedures previously requiring surgery are now done, circumstances permitting, by medical intervention.

This revolution in cardiovascular interventional therapy is regenerative medicine.  It is regenerative because it is largely driven by

• the introduction into the impaired vasculature of an induced pleuripotent cell, called a stem cell, although
• the level of differentiation may not be a most primitive cell line.

There is also a very closely aligned development in cell biology that extends beyond and including vascular regeneration that is called synthetic biology.  These developments have occurred at an accelerated rate in the last 15 years. The methods of interventional cardiology were already well developed in the mid 1980s.  This was at the peak of cardiothoracic bypass surgery.

Research on the endothelial cell,

• endothelial cell proliferation,
• shear flow in small arteries, especially at branch points, and
• endothelial-platelet interactions

led to insights about plaque formation and vessel thrombosis.

Much was learned in biomechanics about the shear flow stresses on the luminal surface of the vasculature, and there was also

• the concomitant discovery of nitric oxide,
• oxidative stress, and
• the isoenzymes of nitric oxide synthase (eNOS, iNOS, and nNOS).

It became a fundamental tenet of vascular biology that

• atherogenesis is a maladjustment to oxidative stress not only through genetic, but also
• non-genetic nutritional factors that could be related to the balance of omega (ω)-3 and omega (ω)-6 fatty acids,
• a pro-inflammatory state that elicits inflammatory cytokines, such as, interleukin-6 (IL6) and c-reactive protein(CRP),
• insulin resistance with excess carbohydrate associated with type 2 diabetes and beta (β) cell stress,
• excess trans- and saturated fats, and perhaps
• the now plausible colonic microbial population of the gastrointestinal tract (GIT).

There is also an association of abdominal adiposity,

• including the visceral peritoneum, with both T2DM and with arteriosclerotic vessel disease,
• which is presenting at a young age, and has ties to
• the effects of an adipokine, adiponectin.

Much important work has already been discussed in the domain of cardiac catheterization and research done to

• prevent atheroembolization.and beyond that,
• research done to implant an endothelial growth matrix.

Even then, dramatic work had already been done on

• the platelet structure and metabolism, and
• this has transformed our knowledge of platelet biology.

The coagulation process has been discussed in detailed in a previous document.  The result was the development of a

• new class of platelet aggregation inhibitors designed to block the activation of protein on the platelet surface that
• is critical in the coagulation cascade.

In addition, the term long used to describe atherosclerosis, atheroma notwithstanding, is “hardening of the arteries”.  This is particularly notable with respect to mid-size arteries and arterioles that feed the heart and kidneys. Whether it is preceded by or develops concurrently with chronic renal insufficiency and lowered glomerular filtration rate is perhaps arguable.  However, there is now a body of evidence that points to

• a change in the vascular muscularis and vessel stiffness, in addition to the endothelial features already mentioned.

This has provided a basis for

• targeted pharmaceutical intervention, and
• reduction in salt intake.

So we have a  group of metabolic disorders, which may alone or in combination,

• lead to and be associated with the long term effects of cardiovascular disease, including
• congestive heart failure.

This has been classically broken down into forward and backward failure,

• depending on decrease outflow through the aorta (ejection fraction), or
• decreased venous return through the vena cava,

which involves increased pulmonary vascular resistance and decreased return into the left atrium.

This also has ties to several causes, which may be cardiac or vascular. This document, as the previous, has four pats.  They are broadly:

1. Stem Cells in Cardiovascular Diseases
2. Regenerative Cell and Molecular Biology
3. Therapeutics Levels In Molecular Cardiology
4. Research Proposals for Endogenous Augmentation of circulating Endothelial Progenitor Cells (cEPCs)

As in the previous section, we start with the biology of the stem cell and the degeneration in cardiovascular diseases, then proceed to regeneration, then therapeutics, and finally – proposals for augmenting therapy with circulating endogenous endothelial progenitor cells (cEPCs).

 

stem cells

 

regeneration

 

 

 

 

Therapeutics

 

augmentation

 

 

 

 

 

 

 

 

 

 

Key pathways involving NO

 

 

 

 

stem cellLlin28

Tranlational Research -Lab to Bedside

 

 

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Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Posted in Cell Biology, Signaling & Cell Circuits, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Human Immune System in Health and in Disease, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Innovation in Immunology Diagnostics, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nephrology, Nephrology & Regenerative medicine, Neurohumoral Transmission, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Signaling, Systemic Inflammatory Response Related Disorders, Water Transporters on March 3, 2014| Leave a Comment »

Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Curator: Aviva Lev-Ari, PhD, RN

Article ID #118: Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension. Published on 3/3/2014

WordCloud Image Produced by Adam Tubman

 

Yale’s Lifton receives $3 million science prize at gala Silicon Valley ceremony

Friday, December 13, 2013

Bill Hathaway / 203-432-1322

Read this article on YaleNews

Richard Lifton, Sterling Professor of Genetics and chair of the Department of Genetics, has received a $3 million Breakthrough Prize in Life Sciences, created by top Silicon Valley entrepreneurs.

Lifton was one of eight scientists honored Dec. 12 with $21 million in prizes at gala ceremonies hosted by actor Kevin Spacey in Mountain View, California. Celebrities — including Conan O’Brien, Glenn Close, Rob Lowe, and Michael C. Hall — handed out awards to six winners of the life sciences prizes and two co-winners of the Breakthrough Prize in Fundamental Physics.

“Scientists should be celebrated as heroes, and we are honored to be part of today’s celebration,” said Google co-founder Sergey Brin and his wife, biologist and entrepreneur Anne Wojcicki, two of the event’s sponsors.

Lifton, who is also an investigator for the Howard Hughes Medical Institute, was recognized for his pioneering work to identify the genetic and biochemical underpinnings of hypertension, a disease that affects more than 1 billion people worldwide and that contributes to 17 million deaths annually from heart attack and stroke. Lifton and his colleagues identified patients around the world with exceptionally high or low blood pressure due to single gene mutations. They identified the mutated genes and established their role in salt reabsorption by the kidney and regulation of blood pressure. The work gave scientific rationale to limit dietary salt intake and suggested rational combinations of antihypertensive medications and development of new therapies.

Other sponsors of the event are Chinese internet entrepreneur Jack Ma and Cathy Zhang; Russian entrepreneur and venture capitalist Yuri Milner and his wife, Julia Milner; and Facebook founder Mark Zuckerberg and Priscilla Chan.

At the end of the ceremonies, which will be televised on the Science Channel at 9 p.m. on Jan. 27, Milner and Zuckerberg announced the creation of a $3 million Breakthrough Prize in Mathematics that will be awarded next year.

Additional information on the prizes can be found atwww.breakthroughprizeinlifesciences.org or www.fundamentalphysicsprize.org.

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SOURCE

http://www.bizjournals.com/sanfrancisco/prnewswire/press_releases/California/2013/12/13/NY33121

THE DISCOVERY

Laliotis MD, Zhang J, Volkman HM, Kahle KT, Hoffmann, KE, Toka HR, Nelson-Williams C, Ellison, DH, Flavell, R, Booth, CJ, Lu Y, Geller, DS, Lifton, RP. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nature Genetics, in press

Earlier Research Results on this discovey

Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4. Epub 2003 Jan 6.

Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.

Wilson FH¹, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP.

Author information

Abstract

Mutations in the serine-threonine kinases WNK1 and WNK4 [with no lysine (K) at a key catalytic residue] cause pseudohypoaldosteronism type II (PHAII), a Mendelian disease featuring hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. Both kinases are expressed in the distal nephron, although the regulators and targets of WNK signaling cascades are unknown. The Cl(-) dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a “mirror image” of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling. To address this possibility, we measured NCCT-mediated Na(+) influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes. Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4). This inhibition depends on WNK4 kinase activity, because missense mutations that abrogate kinase function prevent this effect. PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder. The specificity of this effect is indicated by the finding that WNK4 and the carboxyl terminus of NCCT coimmunoprecipitate when expressed in HEK 293T cells. Together, these findings demonstrate that WNK4 negatively regulates surface expression of NCCT and implicate loss of this regulation in the molecular pathogenesis of an inherited form of hypertension.

Free PMC Article

Images from this publication.See all images (4)Free text

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/12515852

LISTEN TO AUDIO TAPE by Prof. Richard Lifton

http://streaming.yale.edu/opa/podcasts/audio/schools/health_and_medicine/lifton_092007.mp3

January 27, 2014

Richard Lifton

Yale’s Richard Lifton is one of eight world-changing researchers whose work is celebrated during a program airing tonight (Jan. 27) on the Science Channel at 9 p.m. EST.

Lifton, Sterling Professor of Genetics and chair of the Department of Genetics, received a $3 million Breakthrough Prize in Life Sciences, created by top Silicon Valley entrepreneurs.

The Science Channel program features the Dec. 12 ceremony where Lifton and others received their prize. The festivities were hosted by actor Kevin Spacey and featured such celebrities as Conan O’Brien, Glenn Close, Rob Lowe, and Michael C. Hall, as well as tech leaders Mark Zuckerberg, Larry Page, Sergey Brin, Anne Wojcicki, Jimmy Wales, and Yuri Milner.

SOURCE

http://news.yale.edu/2014/01/27/tonight-lifton-honored-star-studded-ceremony

Yale consortium awarded $6 million to study therapies for vascular disease

Tuesday, January 21, 2014

---

Contact

Helen Dodson / 203-436-3984

Stacey Buba / 203-432-1333

Read this article on YaleNews

An international research team spearheaded by William C. Sessa, the Alfred Gilman Professor of Pharmacology and professor of medicine (cardiology), has been awarded a $6 million Transatlantic Networks of Excellence grant from the Fondation Leducq in France.

Sessa will be the U.S. coordinator for the consortium as it explores the mechanisms of secreted microRNAs and microRNA-based therapies for vascular disease. Sessa will be joined by a European coordinator, Dr. Thomas Thum, director of the Institute for Molecular and Translational Therapeutic Strategies at Hanover Medical School in Germany, and five investigators including recent Yale recruit, Carlos Fenandez-Hernando, associate professor of comparative medicine. The grant will be distributed over five years.

Sessa is director of the vascular biology and therapeutics program and vice chairman of pharmacology at Yale School of Medicine.

Sessa has long worked at the intersection of pharmacology and cardiovascular disease. He is on the scientific advisory board of the William Harvey Research Institute and NIHR Biomedical Research Unit in London, and also served on the joint strategy committee for the Yale-UCL collaborative in cardiovascular research.

“I am grateful to Fondation Leducq for funding this new international collaboration to find new and effective ways to treat a disease that kills millions of people each year,” Sessa said. “We have assembled a fantastic team of world class scientists to tackle the basic questions of how microRNAs are packaged and transferred between cells, and their therapeutic potential in vascular diseases.”

Fondation Leducq is a French non-profit health research foundation. Its mission is to improve human health through international efforts to combat cardiovascular disease. To this end, Fondation Leducq created the Transatlantic Networks of Excellence in Cardiovascular Research Program, which is designed to promote collaborative research involving centers in North America and Europe in the areas of cardiovascular and neurovascular disease.

Yale has had two previous Leducq grants — to Dr. Richard Lifton, chair of genetics, and Dr. Michael Simons, director of the Yale Cardiovascular Research Center.

SOURCE

http://bbs.yale.edu/about/article.aspx?id=6569

International Activity

• YALE-UCL Collaborative
  London, United Kingdom (2011)
  Dr. Lifton is on the Joint Strategy Committee for the Yale-UCL Collaborative, an alliance which will provide opportunities for high-level scientific research, clinical and educational collaboration across the institutions involved: Yale University, Yale School of Medicine, Yale-New Haven Hospital and UCL (University College London) and UCL Partners
• Transatlantic Network on Hypertension-Renal Salt Handling in the Control of Blood Pressure
  France (2007)
  Drs Hebert and Lifton will join leading researchers in Switzerland, France and Mexico in a transatlantic collaboration aimed at pinpointing the kidney’s role in high blood pressure.

---

Education & Training

M.D.

Stanford University (1982)

Ph.D.

Stanford University (1986)

---

Honors & Recognition

• National Academy of Sciences
• The Basic Science Prize
  American Heart Association
• Homer Smith Award
  American Society of Nephrology
• MSD International Award
  International Society of Hypertension

Research Interests

Molecular genetics of common human diseases

---

Research Summary

The common human diseases that account for the vast majority of morbidity and mortality in human populations are known to have underlying inherited components. Advances in human genetics have made the identification of genetic variants contributing to these traits feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders. We have focused on cardiovascular and renal disease. To date, we have identified mutations underlying more than 20 human diseases; these include a host of diseases that define molecular determinants of hypertension, stroke and heart attack. We have gone on from these starting points to use biochemistry and animal models to define the physiologic mechanisms linking genotype and phenotype. These findings have provided new insight into normal and disease biology, are identifying new pathways underlying disease pathogenesis, and are identifying new targets for development of novel therapeutics.

Extensive Research Description

Cardiovascular disease is the leading cause of death world-wide. Epidemiologic studies have identified hypertension, high cholesterol, diabetes and smoking as major risk factors. By investigation of rare families recruited from around the world that segregate single genes with large effect, we have identified genes that contribute to these traits, putting a molecular face on their pathogenesis. For example, we have identified mutations in 8 genes that cause high blood pressure (hypertension) and another 8 that cause low blood pressure. These mutations all converge on a final common pathway, the regulation of net salt reabsorption in the kidney. These findings have established the key role of variation in renal salt handling in blood pressure variation, and have led to changes in the approach to treatment of this disease in the general population. They have also identified new therapeutic targets that are predicted to have greater efficacy with reduced side effects. Finally, they have identified new signaling pathways involved in the regulation of blood pressure homeostasis. We have taken similar approaches to another common disease, osteoporosis, with the identification of gain of function mutations in LRP5, a component of the Wnt signaling pathway, in development of high bone density. This finding has led to intensive efforts to identify small molecules that impact this pathway to protect against and/or reverse osteoporosis in the general population. Ongoing studies use both emerging and novel approaches to identification of genes that contribute to disease burden in the population, and to understanding the pathways that link genes to disease. Mutations that affect blood pressure in humans. A diagram of a nephron, the filtering unit of the kidney, is shown. The molecular pathways mediating NaCl reabsorption in individual renal cells along the nephron are shown, along with the pathway of the renin-angiotensin system, a major regulator of renal salt reabsorption. Inherited diseases affecting these pathways are indicated, with hypertensive disorders in red and hypotensive disorders in blue. From Lifton, Gharavi, and Geller. Cell, 104:545-556, 2001.

---

Selected Publications

• Mani, A., et al. (2007). LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278-82.
• Ring, A.M., et al. (2007). An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proc. Natl. Acad. Sci. (USA) 104:4025-9.
• Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann, KE, Toka HR, Nelson-Williams C, Ellison, DH, Flavell, R, Booth, CJ, Lu Y, Geller, DS, Lifton, RP. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nature Genetics, in press.
• Wilson FH, Hariri A, Farhi A, Zhao H, Peterson K, Toka HR, Nelson- Williams C, Raja KM, Kashgarian M, Shulman GI, Scheinman SJ, Lifton RP. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science, 306:1190-94, 2004.
• Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related protein 5. New Engl J Med. 346:1513-1521, 2002.
• Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human Hypertension Caused by Mutations in WNK Kinases. Science, 293:1107-1112, 2001.
• Lifton RP, Gharavi A, Geller DS. Molecular mechanisms of human hypertension. Cell, 104:545-556, 2001.
• Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai TF, Sigler P, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science, 289:119-123, 2000.
• Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science, 285:103-106, 1999.

SOURCE
http://bbs.yale.edu/people/richard_lifton-3.profile

PubMed Results: 10

Select item 225138461.

Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels.

Lin DH, Yue P, Rinehart J, Sun P, Wang Z, Lifton R, Wang WH.

Am J Physiol Renal Physiol. 2012 Jul 1;303(1):F110-9. doi: 10.1152/ajprenal.00676.2011. Epub 2012 Apr 18.

PMID:

22513846

[PubMed – indexed for MEDLINE]

Free PMC Article

Related citations

Select item 165287062.

Haplotype analysis in the presence of informatively missing genotype data.

Liu N, Beerman I, Lifton R, Zhao H.

Genet Epidemiol. 2006 May;30(4):290-300.

PMID:

16528706

[PubMed – indexed for MEDLINE]

Related citations

Select item 165282533.

Familial aggregation of primary glomerulonephritis in an Italian population isolate: Valtrompia study.

Izzi C, Sanna-Cherchi S, Prati E, Belleri R, Remedio A, Tardanico R, Foramitti M, Guerini S, Viola BF, Movilli E, Beerman I, Lifton R, Leone L, Gharavi A, Scolari F.

Kidney Int. 2006 Mar;69(6):1033-40.

PMID:

16528253

[PubMed – indexed for MEDLINE]

Related citations

Select item 127823554.

Mice lacking the B1 subunit of H+ -ATPase have normal hearing.

Dou H, Finberg K, Cardell EL, Lifton R, Choo D.

Hear Res. 2003 Jun;180(1-2):76-84.

PMID:

12782355

[PubMed – indexed for MEDLINE]

Related citations

Select item 113430495.

Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood.

Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R.

J Pediatr. 2001 May;138(5):715-20.

PMID:

11343049

[PubMed – indexed for MEDLINE]

Related citations

Select item 102327426.

Elevated ambulatory blood pressure in 20 subjects with Williams syndrome.

Broder K, Reinhardt E, Ahern J, Lifton R, Tamborlane W, Pober B.

Am J Med Genet. 1999 Apr 23;83(5):356-60.

PMID:

10232742

[PubMed – indexed for MEDLINE]

Related citations

Select item 97986657.

Coincident acute myelogenous leukemia and ischemic heart disease: use of the cardioprotectant dexrazoxane during induction chemotherapy.

Woodlock TJ, Lifton R, DiSalle M.

Am J Hematol. 1998 Nov;59(3):246-8.

PMID:

9798665

[PubMed – indexed for MEDLINE]

Related citations

Select item 95012578.

In vivo phosphorylation of the epithelial sodium channel.

Shimkets RA, Lifton R, Canessa CM.

Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3301-5.

PMID:

9501257

[PubMed – indexed for MEDLINE]

Free PMC Article

Related citations

Select item 91562619.

Autotransplantation for relapsed or refractory non-Hodgkin’s lymphoma (NHL): long-term follow-up and analysis of prognostic factors.

Rapoport AP, Lifton R, Constine LS, Duerst RE, Abboud CN, Liesveld JL, Packman CH, Eberly S, Raubertas RF, Martin BA, Flesher WR, Kouides PA, DiPersio JF, Rowe JM.

Bone Marrow Transplant. 1997 May;19(9):883-90.

PMID:

9156261

[PubMed – indexed for MEDLINE]

Free Article

Related citations

Select item 881130410.

Clinical use of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in neutropenia associated with malignancy.

Lifton R, Bennett JM.

Hematol Oncol Clin North Am. 1996 Aug;10(4):825-39. Review.

PMID:

8811304

[PubMed – indexed for MEDLINE]

Related citations

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&itool=pubmed_AbstractPlus&term=%22Lifton+R%22%5BAuthor%5D

 

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The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Posted in Accountable Care Organizations, Affordable Care Act, Anemia, Atherogenic Processes & Pathology, Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Ca2+ triggered activation, Ca2+ triggered activation, Calcium Signaling, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Curation, Curation methodology, Cytoskeleton, Diabetes Mellitus, Electrophysiology, Evidence-based decision-making, Experimental validation, Federal Budget Appropriations, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, Healthcare Reform, Historical relevance, HTN, HTN in Youth, Indigent Nutrition, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Medicare and Medicaid, Na-K transport, Na-K-ATPase, Nephrology, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Regenerative Biology and Medicine, Resident-cell-based, Skilled Nursing Facilities, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systematic Error (Bias), Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, Uninsured and Underinsured, Valves & Tools, tagged acute myocardial infarct, American College of Cardiology ACC, Antiarrhythmic drugs, arrythmias, Artificial Biosensor, Artificial cardiac pacemaker, Artificial heart, Bare-metal stent, Cardiac & Vascular Repair, cardiac myocyte regeneration, Cardiogenic Shock, Cardiology, Cardiometabolic Syndrome, CHF, Content Curation, Coronary artery disease, Coronary stent, Curation methodology, Drug-eluting stents, gene expression, Hypertension, myocardial hypertrophy, nitric oxide, Nitric oxide synthase, RNA, Stem cell on January 1, 2014| Leave a Comment »

The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Author: Larry H. Bernstein, MD, FCAP

Article ID #98: The Cost to Value Conundrum in Cardiovascular Healthcare Provision. Published on 1/1/2014

WordCloud Image Produced by Adam Tubman

I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:

1. Pathogenesis
2. Diagnosis
3. Treatment

Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances.  Curation requires:

• meaningful selection,
• enrichment, and
• sharing combining sources and
• creation of new synnthesis

Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.

Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities.  It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)).  One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions.  One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care.  This is a holdout that persists in for-profit managed care as an option.  A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.

In this respect, the problem is not simple, but is resolvable.  A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.

http://macro-economic-design.blogspot.com/p/book.html

Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed.  If we tie together Part 1 and Part 2, there is ample room for considering  clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.  Why should this be?  Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.

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

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 on December 21, 2013| Leave a Comment »

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.

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

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