John Newman - US grants

DESCRIPTION (provided by applicant): This application for the Paul B. Beeson Clinical Scientist Development Award in Aging (K08) describes the five-year career development plan of Dr. John Newman, a geriatrician and young physician-scientist in the Division of Geriatrics at the University of California, San Francisco. Dr. Newman's long-term career goal is to elucidate the mechanisms of pathways that broadly regulate healthspan and longevity in mammals, and translate these advances into therapies targeted at elders at high risk for frailty, cognitive decline, and functional dependence. The specific career development goals outlined in this application include developing expertise in the study of mitochondrial and cellular metabolism, deacetylases and histone modifications; the assessment of metabolic health and behavioral function in mouse model systems; and the translational application of aging biology. The primary mentor for accomplishing these career development goals is Dr. Eric Verdin, Professor of Medicine at UCSF and Senior Investigator at the Gladstone Institutes, a world-renowned expert on cellular metabolism, protein acylation, and the biology of aging. Dr. Verdin will be assisted by co-mentor Dr. Michael Steinman, Associate Professor, Director of Research Training, and Co-Director of Research in the UCSF Division of Geriatrics, and an accomplished physician-scientist. The career development plan of Dr. Newman includes individualized mentorship with his mentorship team, formal coursework, and a research program that builds upon Dr. Newman's prior experience in geriatrics, molecular biology, and bioinformatics with thorough training in metabolism, protein biochemistry, and mouse behavioral analysis. The overall objective of the research plan is to elucidate the biological effects of histone deacetylas inhibition by ß-hydroxybutyrate (BOHB), the major ketone body in humans. BOHB is produced from stored fat during fasting or strenuous exercise. Work in Dr. Verdin's laboratory recently found that BOHB inhibits deacetylases in vitro and in vivo and causes up-regulation of oxidative stress-response genes in the mouse kidney. The central hypothesis of this project is that BOHB is an endogenous epigenetic mediator of some of the health and longevity benefits of calorie restriction. The specific aims of the project include systematically mapping changes in gene expression and histone modifications caused by BOHB in various mouse organs; testing the hypothesis that BOHB improves metabolic, cognitive, or neuromuscular health in middle-aged mice; and assessing longevity in mice consistently exposed to BOHB. These aims will permit detailed mechanistic follow-on studies of links between BOHB -regulated genes and phenotypes in specific tissues, with identification of targets that are downstream of BOHB for drug discovery. The application is relevant to NIH and NIA because Dr. Newman's career goal is to leverage an understanding of the multifactorial pathways that regulate aging and longevity to provide translational therapies for the multifactorial geriatric syndromes.

Abstract Vitamin B1 (thiamine) is critical in normal cellular metabolism. Thiamine deficiency diseases, notably wet and dry beriberi, and Wernicke's encephalopathy, a severe neurological syndrome associated with thiamine deficiency, are associated with many diseases and conditions that result from under-nutrition and malabsorption of thiamine (e.g. alcoholism, bariatric surgery) or hyper-metabolic states (e.g., cancer). However mechanistic studies following a recent and disastrous clinical drug trial (that was terminated because the drug, fedratinib, led to Wernicke's encephalopathy) highlighted the importance of pharmaceutical agents as contributors to thiamine deficiency. That is, fedratinib was shown to be a potent inhibitor of thiamine absorption via the thiamine transporter, SLC19A3. In this research application, we bring together NIH and USDA nutrition supported researchers, in response to PAR-15-024. In particular, we propose to test the hypotheses that commonly used medications inhibit SLC19A3-mediated intestinal absorption of thiamine resulting in drug-vitamin interactions. Secondly, we propose that these drug-thiamine interactions produce a detectable metabolic signature that relates to reduction in the activity of enzymes that are dependent on thiamine pyrophosphate (TPP), the active metabolite of thiamine. Our hypotheses are based on exciting preliminary studies in our laboratories demonstrating that several prescription drugs, e.g., metformin, pyrimethamine and amiloride, are inhibitors of SLC19A3. Three aims are proposed: 1. Develop and characterize a humanized transgenic mouse model of SLC19A3 that can serve as an animal model to test drugs for their potential to cause thiamine deficiency. 2. Determine the effects of metformin on the pharmacokinetics and metabolic signatures of thiamine in healthy volunteers using a randomized crossover study; and 3. Use a novel miniaturized assay to screen a 2000-compound library of prescription drugs and bioactives to identify compounds that inhibit SLC19A3 and determine the key structural moieties for SLC19A3 inhibition using quantitative structure activity relationship modeling (QSAR). A multi-tiered approach will be used for the proposed studies including drug-vitamin interaction studies in healthy volunteers; metabolomic methods to identify metabolic signatures of thiamine; small molecule screening to identify inhibitors of SLC19A3; and creation and characterization of humanized mouse models of SLC19A3. Collectively, these novel studies will lead to a new knowledge of drug-vitamin interactions and their metabolic signatures. Specifically, the studies will lead to new tools that can be used in nutrient research and to a recognition that therapeutic drugs may adversely affect thiamine absorption and contribute to thiamine deficiency.