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Posts Tagged ‘NIH’


International Award for Human Genome Project

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The Thai royal family awarded its annual prizes in Bangkok, Thailand, in late January 2018 in recognition of advances in public health and medicine – through the Prince Mahidol Award Foundation under the Royal Patronage. This foundation was established in 1992 to honor the late Prince Mahidol of Songkla, the Royal Father of His Majesty King Bhumibol Adulyadej of Thailand and the Royal Grandfather of the present King. Prince Mahidol is celebrated worldwide as the father of modern medicine and public health in Thailand.

 

The Human Genome Project has been awarded the 2017 Prince Mahidol Award for revolutionary advances in the field of medicine. The Human Genome Project was completed in 2003. It was an international, collaborative research program aimed at the complete mapping and sequencing of the human genome. Its final goal was to provide researchers with fundamental information about the human genome and powerful tools for understanding the genetic factors in human disease, paving the way for new strategies for disease diagnosis, treatment and prevention.

 

The resulting human genome sequence has provided a foundation on which researchers and clinicians now tackle increasingly complex problems, transforming the study of human biology and disease. Particularly it is satisfying that it has given the researchers the ability to begin using genomics to improve approaches for diagnosing and treating human disease thereby beginning the era of genomic medicine.

 

National Human Genome Research Institute (NHGRI) is devoted to advancing health through genome research. The institute led National Institutes of Health’s (NIH’s) contribution to the Human Genome Project, which was successfully completed in 2003 ahead of schedule and under budget. NIH, is USA’s national medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.

 

Building on the foundation laid by the sequencing of the human genome, NHGRI’s work now encompasses a broad range of research aimed at expanding understanding of human biology and improving human health. In addition, a critical part of NHGRI’s mission continues to be the study of the ethical, legal and social implications of genome research.

 

References:

 

https://www.nih.gov/news-events/news-releases/human-genome-project-awarded-thai-2017-prince-mahidol-award-field-medicine

 

http://www.mfa.go.th/main/en/news3/6886/83875-Announcement-of-the-Prince-Mahidol-Laureates-2017.html

 

http://www.thaiembassy.org/london/en/news/7519/83884-Announcement-of-the-Prince-Mahidol-Laureates-2017.html

 

http://englishnews.thaipbs.or.th/us-human-genome-project-influenza-researchers-win-prince-mahidol-award-2017/

 

http://genomesequencing.com/the-human-genome-project-is-awarded-the-thai-2017-prince-mahidol-award-for-the-field-of-medicine-national-institutes-of-health-press-release/

 

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Christopher J. Lynch, MD, PhD, the New Office of Nutrition Research, Director

Curator: Larry H. Bernstein, MD, FCAP

 

Christopher J. Lynch to direct Office of Nutrition Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

http://www.nih.gov/news-events/news-releases/christopher-j-lynch-direct-office-nutrition-research

 

Christopher J. Lynch, Ph.D., has been named the new director of the Office of Nutrition Research (ONR) and chief of the Nutrition Research Branch within the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lynch officially assumed his new roles on Feb. 21, 2016. NIDDK is part of the National Institutes of Health.

Lynch will facilitate nutrition research within NIDDK and — through ONR — across NIH, in part by forming and leading a trans-NIH strategic working group. He will also continue and extend ongoing efforts at NIDDK to collaborate widely to advance nutrition research.

“Dr. Lynch is a leader in the nutrition community and his expertise will be vital to guiding the NIH strategic plan for nutrition research,” said NIH Director Francis S. Collins, M.D., Ph.D.  “As NIH works to expand nutrition knowledge, Dr. Lynch’s understanding of the field will help identify information gaps and create a framework to support future discoveries to ultimately improve human health.”

NIH supports a broad range of nutrition research, including studies on the effects of nutrient and dietary intake on human growth and disease, genetic influences on human nutrition and metabolism and other scientific areas. ONR was established in August 2015 to help NIH develop a strategic plan to expand mission-specific nutrition research.

NARRATIVE:
Our laboratory is dedicated to developing cures for metabolic diseases like Obesity, Diabetes and MSUD. We have several projects:
Project 1: How Antipsychotic Drugs Exert Obesity and Metabolic Disease Side effects
Project 2: Impact of Branched Chain Amino Acid (BCAA) signaling and metabolism in obesity and diabetes.
Project 3: Adipose tissue transplant as a treatment for Maple Syrup Urine Disease.
Project 4: How Gastric Bypass Surgery Provides A Rapid Cure For Diabetes And Other Obesity Co-Morbidities Like Hypertension
Project 5: Novel Mechanism Of Action Of Cannabinoid Receptor 1 Blockers For Improvement Of Diabetes

Timeline

  1. Klingerman CM, Stipanovic ME, Hajnal A, Lynch CJ. Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site. Dose Response. 2015 Oct-Dec; 13(4):1559325815618915.

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  1. Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics. 2015 Nov; 47(11):569-80.

View in: PubMed

  1. Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI. RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats. PLoS One. 2015; 10(4):e0123966.

View in: PubMed

  1. Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, Scherer T, Lindtner C, White PJ, Lapworth AL, Ilkayeva O, Knippschild U, Wolf AM, Scheja L, Grove KL, Smith RD, Qian WJ, Lynch CJ, Newgard CB, Buettner C. Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism. Cell Metab. 2014 Nov 4; 20(5):898-909.

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  1. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014 Dec; 10(12):723-36.

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  1. Olson KC, Chen G, Xu Y, Hajnal A, Lynch CJ. Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats. Obesity (Silver Spring). 2014 May; 22(5):1212-5.

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  1. Zimmerman HA, Olson KC, Chen G, Lynch CJ. Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. Mol Genet Metab. 2013 Aug; 109(4):345-53.

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  1. Olson KC, Chen G, Lynch CJ. Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry. Anal Biochem. 2013 Aug 15; 439(2):116-22.

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  1. She P, Olson KC, Kadota Y, Inukai A, Shimomura Y, Hoppel CL, Adams SH, Kawamata Y, Matsumoto H, Sakai R, Lang CH, Lynch CJ. Leucine and protein metabolism in obese Zucker rats. PLoS One. 2013; 8(3):e59443.

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  1. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys S, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin R, Bettaieb A, Haj FG, Permana P, Anthony TG, Adams SH. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87.

View in: PubMed

  1. Klingerman CM, Stipanovic ME, Bader M, Lynch CJ. Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice. Schizophr Bull. 2014 Mar; 40(2):327-40.

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  1. Carr TD, DiGiovanni J, Lynch CJ, Shantz LM. Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival. Cancer Prev Res (Phila). 2012 Dec; 5(12):1394-404.

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  1. Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1; 302(5):E540-51.

View in: PubMed

  1. Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS One. 2011; 6(8):e22662.

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  1. She P, Zhang Z, Marchionini D, Diaz WC, Jetton TJ, Kimball SR, Vary TC, Lang CH, Lynch CJ. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington’s disease. Am J Physiol Endocrinol Metab. 2011 Jul; 301(1):E49-61.

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  1. Fogle RL, Hollenbeak CS, Stanley BA, Vary TC, Kimball SR, Lynch CJ. Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy. Physiol Genomics. 2011 Apr 12; 43(7):346-56.

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  1. Zhou Y, Jetton TL, Goshorn S, Lynch CJ, She P. Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion. J Biol Chem. 2010 Oct 29; 285(44):33718-26.

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  1. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, Drabick JJ. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract. 2011 Sep; 17(3):197-202.

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  1. Li J, Romestaing C, Han X, Li Y, Hao X, Wu Y, Sun C, Liu X, Jefferson LS, Xiong J, Lanoue KF, Chang Z, Lynch CJ, Wang H, Shi Y. Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab. 2010 Aug 4; 12(2):154-65.

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  1. Culnan DM, Albaugh V, Sun M, Lynch CJ, Lang CH, Cooney RN. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol. 2010 Sep; 299(3):G751-60.

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  1. Hajnal A, Kovacs P, Ahmed T, Meirelles K, Lynch CJ, Cooney RN. Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats. Am J Physiol Gastrointest Liver Physiol. 2010 Oct; 299(4):G967-79.

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  1. Lang CH, Lynch CJ, Vary TC. BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice. Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.

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  1. Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ. Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull. 2012 Jan; 38(1):153-66.

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  1. Fogle RL, Lynch CJ, Palopoli M, Deiter G, Stanley BA, Vary TC. Impact of chronic alcohol ingestion on cardiac muscle protein expression. Alcohol Clin Exp Res. 2010 Jul; 34(7):1226-34.

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  1. Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary TC. Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine. Am J Physiol Endocrinol Metab. 2010 Jun; 298(6):E1283-94.

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  1. Albaugh VL, Judson JG, She P, Lang CH, Maresca KP, Joyal JL, Lynch CJ. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry. 2011 May; 16(5):569-81.

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  1. Lang CH, Lynch CJ, Vary TC. Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase. J Nutr. 2010 May; 140(5):932-8.

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  1. She P, Zhou Y, Zhang Z, Griffin K, Gowda K, Lynch CJ. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance. J Appl Physiol (1985). 2010 Apr; 108(4):941-9.

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  1. Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem. 2010 Apr 9; 285(15):11348-56.

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  1. Li P, Knabe DA, Kim SW, Lynch CJ, Hutson SM, Wu G. Lactating porcine mammary tissue catabolizes branched-chain amino acids for glutamine and aspartate synthesis. J Nutr. 2009 Aug; 139(8):1502-9.

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  1. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009 Jun; 119(6):1678-87.

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  1. Nairizi A, She P, Vary TC, Lynch CJ. Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice. J Nutr. 2009 Apr; 139(4):715-9.

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  1. Meirelles K, Ahmed T, Culnan DM, Lynch CJ, Lang CH, Cooney RN. Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat. Ann Surg. 2009 Feb; 249(2):277-85.

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  1. Culnan DM, Cooney RN, Stanley B, Lynch CJ. Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass. Obesity (Silver Spring). 2009 Jan; 17(1):46-52.

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  1. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007 Dec; 293(6):E1552-63.

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  1. She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. 2007 Sep; 6(3):181-94.

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  1. Vary TC, Lynch CJ. Nutrient signaling components controlling protein synthesis in striated muscle. J Nutr. 2007 Aug; 137(8):1835-43.

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  1. Vary TC, Deiter G, Lynch CJ. Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr. 2007 Aug; 137(8):1857-62.

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  1. Vary TC, Anthony JC, Jefferson LS, Kimball SR, Lynch CJ. Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle. Am J Physiol Endocrinol Metab. 2007 Jul; 293(1):E188-96.

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  1. Vary TC, Lynch CJ. Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts. J Nutr. 2006 Sep; 136(9):2284-90.

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  1. Lynch CJ, Gern B, Lloyd C, Hutson SM, Eicher R, Vary TC. Leucine in food mediates some of the postprandial rise in plasma leptin concentrations. Am J Physiol Endocrinol Metab. 2006 Sep; 291(3):E621-30.

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  1. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, Lynch CJ. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring). 2006 Jan; 14(1):36-51.

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  1. Vary TC, Lynch CJ. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab. 2006 Apr; 290(4):E631-42.

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  1. Vary TC, Goodman S, Kilpatrick LE, Lynch CJ. Nutrient regulation of PKCepsilon is mediated by leucine, not insulin, in skeletal muscle. Am J Physiol Endocrinol Metab. 2005 Oct; 289(4):E684-94.

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  1. Vary TC, Lynch CJ. Biochemical approaches for nutritional support of skeletal muscle protein metabolism during sepsis. Nutr Res Rev. 2004 Jun; 17(1):77-88.

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  1. Lynch CJ, Halle B, Fujii H, Vary TC, Wallin R, Damuni Z, Hutson SM. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003 Oct; 285(4):E854-63.

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  1. Lynch CJ, Hutson SM, Patson BJ, Vaval A, Vary TC. Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab. 2002 Oct; 283(4):E824-35.

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  1. Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 Sep; 283(3):E503-13.

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  1. Vary TC, Lynch CJ, Lang CH. Effects of chronic alcohol consumption on regulation of myocardial protein synthesis. Am J Physiol Heart Circ Physiol. 2001 Sep; 281(3):H1242-51.

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  1. Lynch CJ, Patson BJ, Goodman SA, Trapolsi D, Kimball SR. Zinc stimulates the activity of the insulin- and nutrient-regulated protein kinase mTOR. Am J Physiol Endocrinol Metab. 2001 Jul; 281(1):E25-34.

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Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover.

Lynch CJ1Kimball SR2Xu Y2Salzberg AC3Kawasawa YI4.   Author information
Physiol Genomics. 2015 Nov;47(11):569-80.  http://dx.doi.org:/10.1152/physiolgenomics.00055.2015

Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, α-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and α-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wild-type mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/∼39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

 

RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

Lynch CJ1Xu Y1Hajnal A2Salzberg AC3Kawasawa YI4. Author information
PLoS One. 2015 Apr 20;10(4):e0123966. http://dx.doi.org:/10.1371/journal.pone.0123966. eCollection 2015.

Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side effects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with vehicle or olanzapine for 24h using a dose leading to a mild hyperglycemia. RNA-Seq was performed on gastrocnemius muscle, followed by alignment of the data with the Rat Genome Assembly 5.0. Olanzapine altered expression of 1347 out of 26407 genes. Genes encoding skeletal muscle fiber-type specific sarcomeric, ion channel, glycolytic, O2- and Ca2+-handling, TCA cycle, vascularization and lipid oxidation proteins and pathways, along with NADH shuttles and LDH isoforms were affected. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes (e.g., type 1), while up regulating those for the most glycolytic and least metabolically flexible, fast twitch fiber type, IIb. Protein turnover genes, necessary to bring about transition, were also up regulated. Potential upstream regulators were also identified. Olanzapine appears to be rapidly affecting the muscle transcriptome to bring about a change to a fast-glycolytic fiber type. Such fiber types are more susceptible than slow muscle to atrophy, and such transitions are observed in chronic metabolic diseases. Thus these effects could contribute to the altered body composition and metabolic disease olanzapine causes. A potential interventional strategy is implicated because aerobic exercise, in contrast to resistance exercise, can oppose such slow to fast fiber transitions.

 

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Shin AC1Fasshauer M1Filatova N1Grundell LA1Zielinski E1Zhou JY2Scherer T1Lindtner C1White PJ3Lapworth AL3,Ilkayeva O3Knippschild U4Wolf AM4Scheja L5Grove KL6Smith RD2Qian WJ2Lynch CJ7Newgard CB3Buettner C8. Author information
Cell Metab. 2014 Nov 4;20(5):898-909. http://dx.doi.org:/10.1016/j.cmet.2014.09.003   Epub 2014 Oct 9

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

 

Branched-chain amino acids in metabolic signalling and insulin resistance.

Lynch CJ1Adams SH2Author information
Nat Rev Endocrinol. 2014 Dec; 10(12):723-36. http://dx.doi.org:/10.1038/nrendo.2014.171

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

 

Leucine and protein metabolism in obese Zucker rats.

She P1Olson KCKadota YInukai AShimomura YHoppel CLAdams SHKawamata YMatsumoto HSakai RLang CHLynch CJAuthor information
PLoS One. 2013;8(3):e59443. http://dx.doi.org:/10.1371/journal.pone.0059443   Epub 2013 Mar 20.

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-(14)C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (-21-24%). Plasma BCAAs and BCKAs were elevated 45-69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (-47-66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23-29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193-418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.

 

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity.

Lackey DE1Lynch CJOlson KCMostaedi RAli MSmith WHKarpe FHumphreys SBedinger DHDunn TNThomas APOort PJKieffer DAAmin RBettaieb AHaj FGPermana PAnthony TGAdams SH.
Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87. http://dx.doi.org:/10.1152/ajpendo.00630.2012

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

 

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels.

Lynch CJ1Zhou QShyng SLHeal DJCheetham SCDickinson KGregory PFirnges MNordheim UGoshorn SReiche D,Turski LAntel J.   Author information
Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51.
http://dx.doi.org:/10.1152/ajpendo.00258.2011

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

 

Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion.

Zhou Y1Jetton TLGoshorn SLynch CJShe PAuthor information
J Biol Chem. 2010 Oct 29;285(44):33718-26. http://dx.doi.org:/10.1074/jbc.M110.136846

It remains unclear how α-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and α-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using BCATm(-/-) mice. In static incubation, BCATm disruption abolished insulin secretion by KIC, D,L-α-keto-β-methylvalerate, and α-ketocaproate without altering stimulation by glucose, leucine, or α-ketoglutarate. Similarly, during pancreas perfusions in BCATm(-/-) mice, glucose and arginine stimulated insulin release, whereas KICSIS was largely abolished. During islet perifusions, KIC and 2 mM glutamine caused robust dose-dependent insulin secretion in BCATm(+/+) not BCATm(-/-) islets, whereas LSIS was unaffected. Consistently, in contrast to BCATm(+/+) islets, the increases of the ATP concentration and NADPH/NADP(+) ratio in response to KIC were largely blunted in BCATm(-/-) islets. Compared with nontreated islets, the combination of KIC/glutamine (10/2 mM) did not influence α-ketoglutarate concentrations but caused 120 and 33% increases in malate in BCATm(+/+) and BCATm(-/-) islets, respectively. Although leucine oxidation and KIC transamination were blocked in BCATm(-/-) islets, KIC oxidation was unaltered. These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and α-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to α-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.

 

Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.

Agostino NM1Chinchilli VMLynch CJKoszyk-Szewczyk AGingrich RSivik JDrabick JJ.
J Oncol Pharm Pract. 2011 Sep; 17(3):197-202. http://dx.doi.org:/10.1177/1078155210378913

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRβ are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRβ or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.

 

Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.

Li J1Romestaing CHan XLi YHao XWu YSun CLiu XJefferson LSXiong JLanoue KFChang ZLynch CJWang HShi Y.    Author information
Cell Metab. 2010 Aug 4;12(2):154-65. http://dx.doi.org:/10.1016/j.cmet.2010.07.003

Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1(-/-) mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.

 

BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice.

Lang CH1Lynch CJVary TC.   Author information
Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.
http://dx.doi.org:/10.1152/ajpregu.00297.2010

Endotoxin (LPS) and sepsis decrease mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing protein synthesis. Our study tests the hypothesis that inhibition of branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in muscle protein synthesis. Wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation, eIF4E.eIF4G binding, 4E-BP1.raptor binding, and eIF3.raptor binding without a change in the mTOR.raptor complex in muscle. LPS decreased muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of eIF4E.eIF4G, 4E-BP1.raptor, and eIF3.raptor complexes. In BCATm knockout mice given LPS, muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1.raptor, eIF3.raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle protein synthesis via alterations in protein-protein interactions within mTOR complex-1, and this may provide a survival advantage in response to bacterial infection.

 

Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase.

Lang CH1Lynch CJVary TCAuthor information
J Nutr. 2010 May;140(5):932-8. http://dx.doi.org:/10.3945/jn.109.120501

Acute alcohol intoxication decreases skeletal muscle protein synthesis by impairing mammalian target of rapamycin (mTOR). In 2 studies, we determined whether inhibition of branched-chain amino acid (BCAA) catabolism ameliorates the inhibitory effect of alcohol on muscle protein synthesis by raising the plasma BCAA concentrations and/or by improving the anabolic response to insulin-like growth factor (IGF)-I. In the first study, 4 groups of mice were used: wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout (KO) mice orally administered saline or alcohol (5 g/kg, 1 h). Protein synthesis was greater in KO mice compared with WT controls and was associated with greater phosphorylation of eukaryotic initiation factor (eIF)-4E binding protein-1 (4EBP1), eIF4E-eIF4G binding, and 4EBP1-regulatory associated protein of mTOR (raptor) binding, but not mTOR-raptor binding. Alcohol decreased protein synthesis in WT mice, a change associated with less 4EBP1 phosphorylation, eIF4E-eIF4G binding, and raptor-4EBP1 binding, but greater mTOR-raptor complex formation. Comparable alcohol effects on protein synthesis and signal transduction were detected in BCATm KO mice. The second study used the same 4 groups, but all mice were injected with IGF-I (25 microg/mouse, 30 min). Alcohol impaired the ability of IGF-I to increase muscle protein synthesis, 4EBP1 and 70-kilodalton ribosomal protein S6 kinase-1 phosphorylation, eIF4E-eIF4G binding, and 4EBP1-raptor binding in WT mice. However, in alcohol-treated BCATm KO mice, this IGF-I resistance was not manifested. These data suggest that whereas the sustained elevation in plasma BCAA is not sufficient to ameliorate the catabolic effect of acute alcohol intoxication on muscle protein synthesis, it does improve the anabolic effect of IGF-I.

 

Impact of chronic alcohol ingestion on cardiac muscle protein expression.

Fogle RL1Lynch CJPalopoli MDeiter GStanley BAVary TCAuthor information
Alcohol Clin Exp Res. 2010 Jul;34(7):1226-34. http://dx.doi.org:/10.1111/j.1530-0277.2010.01200.x

BACKGROUND:

Chronic alcohol abuse contributes not only to an increased risk of health-related complications, but also to a premature mortality in adults. Myocardial dysfunction, including the development of a syndrome referred to as alcoholic cardiomyopathy, appears to be a major contributing factor. One mechanism to account for the pathogenesis of alcoholic cardiomyopathy involves alterations in protein expression secondary to an inhibition of protein synthesis. However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved.

METHODS:

The purpose of this study was to examine the effect of chronic alcohol consumption on the expression of cardiac proteins. Male rats were maintained for 16 weeks on a 40% ethanol-containing diet in which alcohol was provided both in drinking water and agar blocks. Control animals were pair-fed to consume the same caloric intake. Heart homogenates from control- and ethanol-fed rats were labeled with the cleavable isotope coded affinity tags (ICAT). Following the reaction with the ICAT reagent, we applied one-dimensional gel electrophoresis with in-gel trypsin digestion of proteins and subsequent MALDI-TOF-TOF mass spectrometric techniques for identification of peptides. Differences in the expression of cardiac proteins from control- and ethanol-fed rats were determined by mass spectrometry approaches.

RESULTS:

Initial proteomic analysis identified and quantified hundreds of cardiac proteins. Major decreases in the expression of specific myocardial proteins were observed. Proteins were grouped depending on their contribution to multiple activities of cardiac function and metabolism, including mitochondrial-, glycolytic-, myofibrillar-, membrane-associated, and plasma proteins. Another group contained identified proteins that could not be properly categorized under the aforementioned classification system.

CONCLUSIONS:

Based on the changes in proteins, we speculate modulation of cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions.

 

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NIMHD welcomes nine new members to the National Advisory Council on Minority Health and Health Disparities

Reporter: Stephen J. Williams, Ph.D.

The National Institute on Minority Health and Health Disparities (NIMHD) has announced the appointment of nine new members to the National Advisory Council on Minority Health and Health Disparities (NACMHD), NIMHD’s principal advisory board. Members of the council are drawn from the scientific, medical, and lay communities, so they offer diverse perspectives on minority health and health disparities.

The NACMHD, which meets three times a year on the National Institutes of Health campus, Bethesda, Maryland, advises the secretary of Health and Human Services and the directors of NIH and NIMHD on matters related to NIMHD’s mission. The council also conducts the second level of review of grant applications and cooperative agreements for research and training and recommends approval for projects that show promise of making valuable contributions to human knowledge.

The next meeting of the NACMHD will be held on Thursday, Sept. 10, 8:30 a.m.-5:00 p.m. on the NIH campus. The meeting will be available on videocast at http://www.videocast.nih.gov.

NIMHD Director Eliseo J. Pérez-Stable, M.D., is pleased to welcome the following new members

Margarita Alegría, Ph.D., is the director of the Center for Multicultural Mental Health Research at Cambridge Health Alliance and a professor in the department of psychiatry at Harvard Medical School, Boston. She has devoted her career to researching disparities in mental health and substance abuse services, with the goal of improving access to and equity and quality of these services for disadvantaged and minority populations.

Maria Araneta, Ph.D., a perinatal epidemiologist, is a professor in the Department of Family and Preventive Medicine at the University of California, San Diego. Her research interests include maternal/pediatric HIV/AIDS, birth defects, and ethnic health disparities in type 2 diabetes, regional fat distribution, cardiovascular disease, and metabolic abnormalities.

Judith Bradford, Ph.D., is director of the Center for Population Research in LGBT Health and she co-chairs The Fenway Institute, Boston. Dr. Bradford has participated in health research since 1984, working with public health programs and community-based organizations to conduct studies on lesbian, gay, bisexual, and transgender people and racial minority communities and to translate the results into programs to reduce health disparities.

Linda Burhansstipanov, Dr.P.H., has worked in public health since 1971, primarily with Native American issues. She is a nationally recognized educator on cancer prevention, community-based participatory research, navigation programs, cultural competency, evaluation, and other topics. Dr. Burhansstipanov worked with the Anschutz Medical Center Cancer Research Center — now the University of Colorado Cancer Research Center — in Denver for five years before founding Native American Cancer Initiatives, Inc., and the Native American Cancer Research Corporation.

Sandro Galea, M.D., a physician and epidemiologist, is the dean and a professor at the Boston University School of Public Health. Prior to his appointment at Boston University, Dr. Galea served as the Anna Cheskis Gelman and Murray Charles Gelman Professor and chair of the Department of Epidemiology at the Columbia University Mailman School of Public Health, New York City. His research focuses on the causes of brain disorders, particularly common mood and anxiety disorders, and substance abuse.

Linda Greene, J.D., is Evjue Bascom Professor of Law at the University of Wisconsin–Madison Law School. Her teaching and academic scholarship include constitutional law, civil procedure, legislation, civil rights, and sports law. Most recently, she was the vice chancellor for equity, diversity, and inclusion at the University of California, San Diego.

Ross A. Hammond, Ph.D., a senior fellow in the Economic Studies Program at the Brookings Institution, Washington, D.C., is also director of the Center on Social Dynamics and Policy. His primary area of expertise is using mathematical and computational methods from complex systems science to model complex dynamics in economic, social, and public health systems. His current research topics include obesity etiology and prevention, tobacco control, and behavioral epidemiology.

Hilton Hudson, II, M.D., is chief of cardiothoracic surgery at Franciscan Healthcare, Munster, Indiana and a national ambassador for the American Heart Association. He also is the founder of Hilton Publishing, Inc., a national publisher dedicated to producing content on solutions related to health, wellness, and education for people in underserved communities. Dr. Hilton’s book, “The Heart of the Matter: The African American Guide to Heart Disease, Heart Treatment and Heart Wellness” has impacted at-risk patients nationwide.

Brian M. Rivers, Ph.D., M.P.H., currently serves on the research faculty at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. He is also an assistant professor in the Department of Oncologic Sciences at the University of South Florida College of Medicine, Tampa. Dr. Rivers’ research efforts include examination of unmet educational and psychosocial needs and the development of communication tools, couple-centered interventions, and evidence-based methods to convey complex information to at-risk populations across the cancer continuum.

NIMHD is one of NIH’s 27 Institutes and Centers. It leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information about NIMHD, visit http://www.nimhd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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ENCODE (Encyclopedia of DNA Elements) program: ‘Tragic’ Sequestration Impact on NHGRI Programs

Reporter: Aviva Lev-Ari, PhD, RN

NHGRI’s Green Sees ‘Tragic’ Sequestration Impact on NHGRI Programs

September 13, 2013

NEW YORK (GenomeWeb News) – The funding squeeze from the sequestration of the US federal budget, now more than half-a-year old, has already had a sizable impact at the National Human Genome Research Institute, leading to cuts to ongoing programs, scaling back of new ones, and the deferring of efforts that have not yet launched.

The five percent cut in funding this year at NHGRI has led not only to trimmed-down renewal grants and fewer, smaller awards broadly, but also has chopped the budget for some of the institute’s important programs, according to NHGRI Director Eric Green.

The programs that have either had their funding reduced, and in one case delayed, include the ENCODE (Encyclopedia of DNA Elements) program, projects focused on using genome sequencing in newborns and in clinical medicine, and other initiatives, Green said in his Director’s Report to the National Advisory Council on Human Genomics Research this week.

In addition, many renewal grants have been trimmed, and there are “numerous examples of detrimental cuts” to the institute’s intramural research program, said Green. These cuts to large and small NHGRI programs come at a pivotal time for genomics, he noted, as the products of such research are beginning to translate into clinical possibilities.

“It is tragic. [That] is the word I would use,” Green told GenomeWeb Daily News this week.

“[The field of genomics] is just so exciting. There are so many opportunities,” he said. “This is precisely the time that we should be pushing the accelerator hard, and we just cannot do it because we don’t have enough fuel in our fuel tank.

“It’s frustrating. I think the opportunities now are just spectacular,” said Green. “It’s tragic because it is just so obvious that we could do some remarkable things in genomics and we are not being able to do it.”

ENCODE, a decade-old flagship project at NIH that aims to identify all of the functional elements in the human genome, had its budget reduced by 16 percent.

The Genomic Sequencing and Newborn Screening Disorders program was cut by half, which left the program to fund fewer research projects than planned and its research consortium to go forward without the benefit of a data coordinating center. This new initiative, an effort to support pioneering studies on how sequencing might be used in the care of newborns and in neonatal care that was created jointly with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, had its budget cut from $10 million to $5 million.

The Genomic Medicine Pilot Demonstration Projects program had its budget cut by 20 percent, and NHGRI’s Bioinformatics Resources and Analysis Research Portfolio had $5 million sliced out of its budget. The new Genomics of Gene Regulation (GGR)request for applications was bumped out of this funding year entirely, and has been delayed until 2014, according to Green.

Because the sequestration plan was concocted and agreed to well in advance of its arrival earlier this year, Green told GWDN that the institute did have some time to try to react to the sequestration and mitigate the pain from the cuts, spreading them around fairly and evenly while maintaining priorities. He said leadership at the institute tried to prepare for the possibility of sequestration by being conservative in its planning.

Programs that were already ongoing, like ENCODE, were likely to take priority over those that were not yet launched, like GGR, in part because the infrastructure is already in place for ongoing projects and because it is easier to plan for how they operate and generate outputs, like data.

“With ENCODE you know for every million dollars you invest you get so much back,” said Green. “With a program like newborn sequencing … we don’t totally know what it’s going to look like or play out like. We won’t know what we are missing because we won’t be able to launch it to the scale that we wanted to launch it originally.”

Green said some of the projects being cut or delayed were created under NHGRI’sstrategic plan, a program it laid out in 2011 that involves restructuring of the institute’s divisions and some shifting in its research portfolio to include more efforts in applying genomics to medicine and healthcare.

“Some of these RFAs that we delayed really represent key elements that we started to anticipate two years ago,” said Green. “We knew we wanted to do more in sequencing, we knew we wanted to do some pilot projects in genomic medicine. We knew we wanted to continue to accelerate efforts in understanding how the genome works … ENCODE, GGR, and so forth. It just had to be slowed down,” he said.

Anastasia Wise, program director for the Genomic Sequencing and Newborn Screening Disorders program, told GWDN that the program was supposed to be much larger than the $5 million in awards unveiled last week, which funded a consortium of four research projects.

Wise said NHGRI and NICHD were each initially planning to provide double the amount of funding they were actually awarded, which is now expected to be a total of $25 million over five years, although that total could be subject to the availability of funding.

“There were definitely more scientifically meritorious applications than we were able to fund,” she said. “Even the four awards that we made ended up being cut an additional five percent because of the sequestration.”

She said the program “wanted to be able to make more awards, and we wanted to be able to fund a coordinating center to be able to bring the network together and help provide some harmonization of data and coordination of logistics between the different members of the consortium,” but it was unable to fund that part of the effort.

Although the fractured fiscal culture in Washington engenders caution at NHGRI as the agency looks forward, Green sees many scientific opportunities right now, as genomics begins to hit the clinic.

“Some people are saying we are not even going fast enough,” he said. “Lots of people have been discussing what the world is going to look like when somebody gets their genome sequenced in the newborn period, and [they] think about what the implications of that are for the patient for the rest of their lives. We want to start studying this,” he said.

“And we are starting to … but we’re not starting as aggressively as we wanted to,” Green said. “I mean, we took a big hit this year.”

Matt Jones is a staff reporter for GenomeWeb Daily News. He covers public policy, legislation, and funding issues that affect researchers in the genomics field, as well as the operations of research institutes. E-mail Matt Jones or follow GWDN’s headlines at @DailyNewsGW.

Related Stories

SOURCE

http://www.genomeweb.com//node/1280236?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Sequestration%20Impact%20on%20NHGRI;%20Adaptive%20Biotechnologies%20Gets%20$2.5M%20SBIR%20Grant;%20In%20Brief;%20People%20-%2009/13/2013%2004:10:00%20PM

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Reporter: Aviva Lev-Ari, PhD,RN

 

Functional Genomics Screening Strategies: Part One

Utilizing RNA Interference (RNAi) Screens

to Explore Drug Targets and Cellular Pathways

Boston, MA | September 24-25, 2013

Dr. Scott Martin, Team Leader for RNAi Screening at NIH’s Chemical Genomics Center, to Present “Swimming in the Deep End – Sources Leading to a False Sense of Security in RNAi Screen Data” at Functional Genomics Screening Strategies Conference

There has been a growing skepticism surrounding RNAi data and the validity of hits arising from largescale RNAi screens. Much of this comes from a lack of agreement between screens conducted in similar biological systems and difficulty in validating published screen hits. In light of these realities, we must rethink some widely held beliefs about screening and validation strategies. These issues and relevant data will be discussed.

 

Functional Genomics Screening Strategies: Part Two

Exploring Novel Screening Platforms and Cellular

Models for Next-Generation Screens

Boston, MA | September 25-26, 2013

The second half of Functional Genomics Screening Strategies will explore the use of chemical genomics screens, microRNA (miRNA) and long non-coding RNA (lncRNA) screens and the transition into advanced cellular models such as, 3D cell cultures, co-cultures and stem cells that will launch the next generation of functional screens. Screening experts from pharma/biotech as well as from academic and government labs will share their experiences leveraging the utility of such diverse screening platforms and models for a wide range of applications.

 SOURCE

 

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Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 6/5/2013

GenomeWeb Feature: Researchers Weigh in on Grants in the Time of Sequester

June 05, 2013

NEW YORK (GenomeWeb News) – When Nicholas Navin’s R01 grant to use single-cell sequencing to study tumor evolution in breast cancer was first funded in 2012, it was funded at 83 percent of the requested budget.

Because of the sequester, Navin’s grant now will be cut a further 6 percent. In addition, he has only been given funding for the next three months.

“After those three months, I assume that it will continue to be funded for the rest of the year,” said Navin, an assistant professor at the University of Texas MD Anderson Cancer Center, “but they only give you enough funding to support you for three months.”

The sequester — the across-the-board cuts to the US budget that were implemented at the beginning of March — has led to budget decreases across the federal government, including at research funding agencies like the National Institutes of Health and the National Science Foundation. The cuts exacerbated what was seen by many as an already tight funding situation that was not keeping pace with inflation, making it increasingly difficult for researchers to fund their work.

Steven Salzberg, a professor at Johns Hopkins University School of Medicine, recently had a grant rejected that was ranked in the top 11th percent of applications. In the past, he’s had grants funded that were in the 16th percentile or 17th percentile.

“They are funding, one would hope, grants at the 11th percentile, but not this particular one,” he said. “So you have to resubmit it or you can give up. Those are your two choices.”

As budgets decline and competition for grants increase, researchers are submitting more proposals and are beginning to look elsewhere for funding. At the same time, they are wondering what the effect of sequestration will be on science and scientists, particularly early career investigators. Still, there are steps investigators can take to try to get their proposal to stand out.

Cuts and effect

Because of the sequester, both NIH and NSF have seen their budgets fall about 5 percent. For this fiscal year, NIH’s budget is about $29.15 billion, as compared to $30.86 billion for fiscal year 2012. At the same time, NSF has about $6.9 billion for 2013, compared to last year’s $7.0 billion.

To cope with these decreases, NIH has cut all noncompeting renewals by 4.5 percent, but other changes were mostly left up to the various institutes that comprise NIH. For example, NHGRI, like other parts of NIH, is cutting noncompeting renewals, but it is not touching small grants, which it defines as ones with commitments of $250,000 or less and that typically are funded through R03 or R21 mechanisms. In addition, NHGRI won’t be giving future inflationary increases to competing applications.

“NHGRI deals with such a relatively small number of grants that we can look at each one individually and make decisions on the basis of how that particular application addresses institute aims and what the application needs in order to be successful,” Mark Guyer, the deputy director of NHGRI, told GenomeWeb Daily News. “Almost everything we do is really on a case-by-case basis beyond the across-the-board cuts to non-competing.”

The sequester, though, comes on the heels of years of small increases to funding agencies’ budgets. While the NIH budget went through an unprecedented doubling between about 1998 and 2003, it has since languished, with increases that typically did not keep pace with inflation.

“The field generally was in dire straits [heading into the sequester], given the very low payline by NIH, for example, and even NSF,” said Sarah Tishkoff, a professor at the University of Pennsylvania.

Salzberg noted that the two NIH R01 grants that he already has — awarded prior to the sequester — were cut about 15 percent to 20 percent. This, he added, was done “administratively because of budget reasons, not because of the peer review.”

“Now [the sequester] comes along and makes it even worse,” Tishkoff added.

Overall, NIH has estimated that it will fund nearly 8,300 competing research grants for FY2013, a decrease of about 700 from last year.

NHGRI also said that, in the face of the sequester, it is aiming to keep the average size of the awards it makes for FY2013 similar to the sizes of those it gave out in FY2012 — meaning that it will be giving out fewer total awards. Competition for grants, then, will become increasingly competitive.

“The [scientific] opportunities over the last decade at least and certainly into the foreseeable future are increasing hand over fist … and available funding is not keeping up with that,” Guyer said. “So necessarily things have gotten more competitive, and the sequester approach to managing the federal budget has only exacerbated the competitive aspects of things.”

As fewer proposals get funded and there’s less money to go around, many investigators may find themselves submitting more proposals to a number of funders.

“I am looking at submitting [more] proposals because it looks like funding is tight, and it is going to remain tight,” Salzberg told GWDN. “Unfortunately this produces a vicious cycle where many of us feel like our chances of getting funded are lower, therefore we should submit more proposals, but that then in return reduces the percentage that gets funded.”

It also increases the amount of time researchers spend reviewing proposals.

Others are looking to supplement their funds by turning to alternative funding sources. Navin, for example, is looking at private foundations and other organizations that fund cancer research, such as the Susan G. Komen Foundation or the Damon Runyon Cancer Research Foundation.

There, he said, he may have a few options given that he studies breast cancer. Other researchers, he noted, may not have such options. “I know some of my colleagues that work on colon cancer or some of the more rare cancers like testicular cancer or bladder cancer, they really have a hard time finding funding now,” he said.

In addition, cuts and uncertainty about future reductions in funding could make a lab a precarious place. After such budget cuts or in anticipation of cuts, some labs have slowed down their growth or have even begun to let people go.

Salzberg said that, as a computational biologist, his main expenses are the salaries of the students, postdocs, and staff who power his lab.

“[The funding situation] also makes me much more reluctant to hire postdocs or any new staff because I don’t have any more money coming in. You need more money to hire new people,” he said. He added that he still gets a number of requests from people looking for positions, but “I don’t have the funding for a new postdoc. Until I get some new funding that’s what I’ll keep saying.”

“I’ve seen [colleagues’] grants just get slashed by huge amounts,” Tishkoff added, noting that she’s seen technicians beginning to lose their jobs.”[Investigators] either have to cut some of the staff or they have to cut one of the aims.”

And as grant budgets are cut, researchers have to accomplish their research aims with less, and this often means cutting back on some of the science they would like to have done.

“Because they cut the budget, you have to cut the scope,” Salzberg said. “You still do the work, but you don’t do all the things that you want to do.”

Navin, for example, is looking to use a smaller study size, even though that’ll affect the statistical power of his work.

And that’s for the grants that get funded.

“Some projects just aren’t getting done,” Salzberg added. “[My grant] that wasn’t funded was a different project and we’re not going to do it.”

This, he said, may lead to delays in improvements to healthcare. New treatments and drugs will come, he said, but it may be in 20 years rather than in 10 years or 15 years.

Concern for new investigators

One common fear is that the sequester will disproportionately affect new investigators as they try to start labs and fund them or even dissuade them from pursuing a career in academia.

“It looks like it is disturbing a lot of young people and influencing the way that they are thinking about a potential career,” Guyer said.

Tishkoff added that she is worried that junior scientists will see how the more senior people are struggling to find funding, and opt out. “[New investigators] have to get grants if they want to get tenure. They have to get grants to be successful and to continue to be a scientist in the future,” she said.

“That’s the question that I get over and over again” from students and postdocs, Navin added. “What’s it going to be like in … five to 10 years?”

“I try to stay optimistic and tell them that there will be funding, but it is hard to predict the future,” he said.

Still, junior scientists may look for careers in industry or outside of the research realm.

“I think that when they hear all of this gloom and doom talk going on, it is really discouraging them. And that makes me really worried that we are losing talented scientists,” Tishkoff said. She added that she’s noticed that people with computational biology or bioinformatic backgrounds seem to be heading to industry.

Salzberg added that the field may never even know what it is losing. “People will leave the field — they won’t announce it — they just go get a job doing something else,” he said. “Generally, you lose that [talent] forever because that person doesn’t come back.”

Funding agencies like NIH do have mechanisms in place to try to help new investigators get grants. For example, proposals from new investigators are reviewed separately from ones submitted by established PIs. That way, early-career researchers compete against each other, rather than against those with more experience.

Further, in its policy statement for this fiscal year, NIH said that it would continue to support new investigators applying for R01 grants with success rates similar to those of established PIs.

“I really think they are doing as much as they can, but there is a bottom line,” Tishkoff noted. “If you do not have the money to give out, then it is going to be more and more and more competitive. That’s just how it is.”

NHGRI, in its own policy statement, said that it is “very flexible” in supporting early-stage investigators by not reducing recommended budgets if possible, by giving special consideration when applying for renewals to avoid gaps in funding, and by its Pathway to Independence Awards, which are targeted to postdocs who are moving toward running their own lab.

Outside of federal support, there are also a number of grants that specifically fund new investigators, such as the David and Lucile Packard Foundation Fellowships for Science and Engineering, Burroughs Wellcome Fund Career Awards, or the Sloan Research Fellowship, among others.

Tips for getting a grant

With increased competition for a smaller pot of money, submitting a well-crafted grant proposal might help it stick out from the rest in the pile. While some researchers may be quickly churning out as many proposals as they can, Tishkoff said that approach may not be the best one.

“The fact is it’s now even more competitive, it is even more important that people are taking time to really work on the grants carefully and not try to rush through them,” she told GWDN.

Still, submit a proposal quickly. “Don’t wait to apply for your first grant,” Salzberg said. “Very few people get funded on their first time around. You learn a lot from the reviews you get back.”

For his first grant, Salzberg partnered with a senior colleague to be a co-PI on the grant. “You can learn a lot about grantsmanship that way,” he said. “And then if the senior colleague gets funded, then you get some money out of that.” In addition, “you also learn some of the administrative hoops.”

Once on a grant, investigators begin to be invited to review panels that evaluate such grant proposals. “That’s a very valuable experience,” Salzberg said. “The first couple of times you are on a review panel, you learn a tremendous amount because you see a lot of other people’s grant applications and you see what the reviewers are saying about them.”

Tishkoff said one common problem she’s seen, particularly among new investigators, is that the proposals can feel hurried and too full of jargon. “You’ve got to take your time, write clearly in a manner that a general scientist can understand,” she said, adding that investigators have to sell their idea to a “broad scientific audience [and] make the point of why it is cutting edge and important and advances the field.”

Having other, more senior people look over a proposal is often a key step, she added, saying that she’s seen applications in which there were simple errors like numbers not adding up that could have easily been avoided by having someone else take a look at it.

An oft-overlooked step, by new and established PIs alike, is getting in touch with their program officers. “Start out talking to NIH program people as soon as possible,” Guyer said.

Program officers can provide information on funding mechanisms, initiatives, and budgets, and offer feedback on how project ideas fit within institutes’ priorities. “And we think, at least we tell ourselves, that it can help save people a lot of wasted time,” he added.

Tishkoff said that she typically calls up her program officer when she’s thinking about and applying for a grant to see how her idea fits with what the institute is interested in funding and to discuss a potentially reasonable budget.

“You could say, ‘I am thinking about applying for this, this, and this. Is that something that you or this institute would be interested in funding?'” she said. “And so you can try to aim to make your proposal fit with what their goals are at the moment.”

“Secondly, I always tell them, ‘OK, here’s the budget I have in mind. Is that going to be realistic or not?'” she added.

And once, she said, she was told her budget for what she called an “all-in-one, big giant grant” was too high to be funded. Instead, Tishkoff broke that large, all-inclusive grant into smaller, more focused projects, and she stripped the budgets to the bare bones.

However, not all proposals will be funded, even well-written ones. “There’s no magic bullet here, though, it’s just times are tough,” Salzberg added. “If they are only funding 10 percent of proposals, then whatever happens, 90 percent of them are going to be rejected, so try to be in the top 10 percent, but we can’t all be in the top 10 percent all the time.”

Navin added that those who get rejected should not give up and should keep submitting. “I just think you have to be very optimistic, be an eternal optimist and just keep submitting your grants to as many different funding agencies as possible,” he said. “And eventually, if it is a good idea, it’ll get funded.”

The next fiscal cycle

While fiscal year 2013 is more than half over, the US federal budget for fiscal year 2014 isn’t yet set, so what is in store for research funding — and whether the sequester will continue —isn’t clear.

The Obama administration released its budget proposal for FY 2014 in April, which would replace the sequester. It called for $31.3 billion for the National Institutes of Health — an increase of 1.5 percent over the FY 2012 budget — and $7.6 billion for the National Science Foundation — an 8.4 percent increase over its FY 2012 appropriation.

The budget, though, needs to pass Congress.

“We’re making plans for FY ’14 on the basis of what the administration presented as a budget,” Guyer said. “We’re hoping the Congress can do better than that. On the other hand, we are realistic.”

Ciara Curtin is GenomeWeb’s science features editor as well as the editor of the Daily Scan and Careers blogs. E-mail Ciara Curtinand follow @DailyScan, and @CareersGW on Twitter.

Fact sheet: Impact of Sequestration on the National Institutes of Health

The National Institutes of Health is the nation’s medical research agency and the leading supporter of biomedical research in the world. NIH’smission is to seek fundamental knowledge about the nature and behavior of living systems and apply that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. Due in large measure to NIH research, a person born in the United States today can expect to live nearly 30 years longer than someone born in 1900.

More than 80 percent of the NIH’s budget goes to over 300,000 research personnel at more than 2,500 universities and research institutions throughout the United States. In addition, about 6,000 scientists work in NIH’s own Intramural Research laboratories, most of which are on the NIH main campus in Bethesda, Md. The main campus is also home to theNIH Clinical Center, the largest hospital in the world totally dedicated to clinical research.

Sequestration:

On March 1, 2013, as required by statute, President Obama signed an order initiating sequestration. The sequestration requires NIH to cut 5 percent or $1.55 billion of its fiscal year (FY) 2013 budget. NIH must apply the cut evenly across all programs, projects, and activities (PPAs), which are primarily NIH institutes and centers. This means every area of medical research will be affected.

NIH FY2013 operating plans:

NIH FY2013 Operating Plan

NIH FY2013 Operating Plan Mechanism Table

NIH Guide Notice: Fiscal Policy for Grant Awards FY2013

NIH Institutes and Centers FY2013 Funding Strategies

The estimated numbers:

(FY 2013 figures compared to FY 2012)

While much of these decreases are due to sequester, NIH funding is always a dynamic situation with multiple drivers:

  • Approximately 700 fewer competitive research project grants issued
  • Approximately 750 fewer new patients admitted to the NIH Clinical Center
  • No increase in stipends for National Research Service Award recipients in FY2013

The impact:

  • Delay in medical progress:
    • Medical breakthroughs do not happen overnight. In almost all instances, breakthrough discoveries result from years of incremental research to understand how disease starts and progresses.
    • Even after the cause and potential drug target of a disease is discovered, it takes on average 13 years and $1 billion to develop a treatment for that target.
    • Therefore, cuts to research are delaying progress in medical breakthroughs, including:
      • development of better cancer drugs that zero in on a tumor with fewer side effects
      • research on a universal flu vaccine that could fight every strain of influenza without needing a yearly shot.
      • prevention of debilitating chronic conditions that are costly to society and delay development of more effective treatments for common and rare diseases affecting millions of Americans.
  • Risk to scientific workforce:
    • NIH drives job creation and economic growth. NIH research funding directly supports hundreds of thousands of American jobs and serves as a foundation for the medical innovation sector, which employs 1 million U.S. citizens. Cuts to NIH funding will have an economic impact in communities throughout the U.S. For every six applications submitted to the NIH, only one will be funded. Sequestration is reducing the overall funding available for grants. See the history of NIH funding success rates.

Frequently asked questions:

How many fewer grants will be awarded?
Approximately 700 fewer research project grants compared to FY 2012.

Have the institutes and centers announced their adjusted paylines based on these cuts?
The adjusted NIH Institute and Center (IC) paylines and funding strategies can be found here:http://grants.nih.gov/grants/financial/index.htm#strategies

What percent cut will be made to existing grants?
Reductions to noncompeting research project grants (RPG) vary depending on the circumstances of the particular IC. The NIH-wide average is -4.7 percent.

Will the duration of existing grants be shortened to accommodate the cuts?
In general, no.

Will all grants receive the same percentage cut or will some grants be cut more than others?
Institutes and centers have flexibility to accommodate the new budget level in a fashion that allows them to meet their scientific and strategic goals. As noted above, there are different percentages for different ICs, and in some cases for different mechanisms within an IC (RPGs, Centers, etc.). In addition, there may be reductions to grants for reasons other than sequestration, as is the case every year.

Will certain areas of science that are at a critical juncture be affected by these cuts? 
All areas of science are expected to be affected.

Will some areas of science be affected more than others?
The sequester does not stipulate the precise reduction to each scientific area. However, it is likely that most scientific areas will be reduced by about 5 percent because the sequester is being applied broadly at the NIH institute and center level.

What will be the impact of these cuts to NIH’s intramural research at its Bethesda campus and off-campus facilities?
The impact on NIH’s intramural research is substantial, especially because it applies retroactively to spending since Oct. 1, 2012. That can double the effect — a full year’s cut has to be absorbed in less than half a year.

Will NIH be furloughing or cutting employees at its NIH campus and off-campus facilities?
There are no current plans to do so. At present, HHS is pursuing non-furlough administrative cost savings such as delayed/forgone hiring and reducing administrative services contracts so that furloughs and layoffs can be avoided. Additionally, employee salaries at NIH make up a very small percentage (only 7 percent) of the NIH budget.

How will current patients at the NIH Clinical Center be affected?
Services to patients will not be reduced.

Will the NIH Clinical Center see fewer patients because of the cuts?
Approximately 750 fewer new patients will be admitted to the NIH Clinical Center hospital in 2013 or a decrease from 10,695 new patients in 2012 to approximately 9,945 new patients in 2013. While much of this decrease is due to funding, clinical activity is always a dynamic situation with multiple drivers.

Will the sequester cut need to be applied to the FY 2014 budget?
The President’s FY 2014 Budget would replace sequestration and reduce the deficit in a balanced way. The President is ready to work with Congress to further reduce deficits while continuing to make critical investments.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

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Reporter: Aviva lev-Ari, PhD, RN

Rock Talk

Helping connect you with the NIH perspective


Diversifying the Training Experiences of the Biomedical Research Workforce

Posted on March 8, 2013 by 

I’m eager to tell you about another important biomedical workforce-related initiative that NIH is launching based on the Advisory Committee to the Director (ACD) working group recommendations. This initiative seeks to expand existing research training and allow research institutions to best prepare their trainees for a variety of research-related career outcomes. The ACD working group report showed that while almost half of US-trained doctorates work in academia, an increasing proportion of newly trained doctorates finds employment opportunities in non-academic sectors and in other research-related occupations.

US-trained doctorates post-training employment as of 2008: 18% non science related, 18% science-related non-research, 6% government research, 18% industry research, 43% academia. NSF Survey of Earned Doctorates data based on 130,000 individuals which is an underestimate of total biomedical research workforce

Especially in challenging financial times, it is important to not only prepare trainees for a diverse set of career outcomes, but to leverage existing resources and enlist additional support from the potential beneficiaries of NIH-supported training – the employers of PhD scientists. TheBroadening Experiences in Scientific Training (BEST) program aims to do just that.

The BEST awards will be piloted through the NIH Common Fund, and support the development of new and innovative methods for preparing graduate students for the full breadth of research and research-related careers in the biomedical, behavioral, social, or clinical sciences. How applicant research institutions choose to approach this may vary. For example, scientific research institutions might initiate mutually beneficial collaborations with schools of business, public policy or economics, or might propose developing partnerships beyond academia and engaging the private sector or non-profit entities. But all programs should introduce students and postdoctoral scientists to the wide array of biomedical careers early in their training, and provide them with experiences in the career they plan to pursue, in addition to their PhD studies and traditional postdoctoral training.

BEST intends to change the culture of biomedical graduate education by seeding the development of diverse training experiences. Up to 15 BEST awards will be made in fiscal year 2013 to support research institutions’ program and administrative needs during the initial stages of development, and to create self-sustaining programs in collaboration with external support. Communication among awardees and rigorous monitoring of outcomes are essential aspects of this award program so that effective and proven models for training can be shared with universities across the United States.

We plan to review applications to the BEST funding opportunity this summer. An informational webinar to advise applicants will be held in March, letters of intent are due in April, and applications are due in May of this year; more details on the program are in the NIH GuideNotice and on the program website.

As the centerpiece of all the ACD biomedical workforce recommendations, this program is an important part of supporting the biomedical research enterprise as a whole, at all stages of the scientific process. This investment is just the beginning of how we prepare biomedical research trainees for a broader set of career options, and I look forward to following the work of BEST awardees as they pioneer these diverse training programs.

 

3 THOUGHTS ON “DIVERSIFYING THE TRAINING EXPERIENCES OF THE BIOMEDICAL RESEARCH WORKFORCE”

  1. It’s fantastic that the ACD is recognizing the need for training and experiential learning outside of pure academic career tracks! I am part of a group of graduate students and postdocs at Washington University School of Medicine who, while looking for an opportunity to gain training and experience, formed a nonprofit consulting company that forms collaborations between early and late stage life sciences companies and small groups of graduate students and postdocs. Through these team strategic consulting projects, all participants whether academic or non-academic focused, receive hands-on, real-world learning experiences. These opportunities train participants in becoming effective communicators, collaborators, leaders, and managers—skills that are often under-developed in many recent graduates and aspiring principal investigators. The group has had tremendous success over the past two years working with 32 companies and 140+ student consultants, many of whom have gone onto academic and non-academic careers and even started their own company. The group also earmarks a significant portion of their revenue for outreach initiatives to support science and career development throughout the community. Importantly, because these projects are inexpensive, the demand for the services is high throughout the country, opening up a huge opportunity for similar initiatives to develop at other universities. Indeed, several groups of graduate students around the U.S are currently taking steps to creating similar initiatives at their institution. We hope the BEST program can foster similar self-sustaining initiatives.

  2. Could anyone from the Rock Talk Blog team comment on why NSF survey data from 2008 is being shown here instead of data from 2011 which was released in December? It would seem to me that the 2011 data would be much more relevant given that 2008 was the start of the recession and that 2% unemployment number back then must have surely risen since then. I would also be curious to see how the percent of people in “Academia” and “Industry research” has changed from 2008 to 2011. My guess is that in the three years from 2008-2011 there have been some dramatic changes in these percentages with “Academia” and “Industry research” comprising now less than 40% combined.

 

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