This proposal details a comprehensive five-year training program for mentored career development (K08) in cardiovascular medicine for Dr. John T. Hinson. The applicant is a prior trainee in the HHMI Medical Fellows program and has completed his clinical training in Cardiovascular Medicine at Brigham and Women's Hospital and Internal Medicine at Massachusetts General Hospital through the ABIM accelerated research pathway. In this proposal, the applicant has outlined a comprehensive research-training program that leverages his prior training in human genetics and metabolism with newly acquired skills in building pluripotent stem cell models of disease, genome editing, metabolomics and flux analysis, and signal transduction, in order to shed novel insight into the mechanisms of AMPK-PRKAG2 associated cardiomyopathy. Dr. Hinson will be under the primary mentorship of Christine E. Seidman, M.D, Thomas W. Smith Professor of Medicine and Genetics at Harvard Medical School and Brigham and Women's Hospital, who is both a distinguished clinical cardiologist and member of the Howard Hughes Medical Institute and National Academy of Sciences. Dr. Seidman and her husband Dr. Jonathan Seidman are world-renown human and molecular geneticists with a focus on cardiovascular genetics. Over the last twenty years, the Seidmans have mentored countless young investigators who go on to successful, independent research careers as physician scientists. Dr. Hinson's career development plan includes educational resources at Harvard Medical School and Brigham and Women's Hospital. In addition to the resources in Dr. Seidman's state-of -the-art laboratory environment, he has gathered an advisory committee that includes world experts in genome editing and next-generation sequencing technology, mitochondrial biology, and signal transduction. The applicant's primary goals are to 1) identify how specific PRKAG2 mutations cause glycogen storage and left ventricular hypertrophy, 2) elucidate how metabolic sensing by AMPK impacts the TGF-beta signaling pathway, and finally 3) target AMPK by chemical activation in other mouse models of cardiomyopathy. Towards this, Dr. Hinson will utilize an innovative iPS model of PRKAG2-N488I cardiomyopathy created with TALEN genome editing, perform a global metabolic assessment with LC-MS combined with flux analysis of labeled substrates, and study signal transduction pathways that connect metabolic sensing by AMPK to AKT and TGF-beta pathways. Going forward, Dr. Hinson will use this career development plan to build the foundation for a career as an independent, academic physician scientist.

Public Health Relevance

Cardiomyopathies are common disorders that cause significant morbidity and mortality and most have no effective therapies. In this proposal, we investigate the mechanism of PRKAG2-cardiomyopathy in a human stem cell model to identify novel therapeutic targets for this and other forms of cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL125807-05
Application #
9391028
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Wang, Wayne C
Project Start
2014-12-15
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281
Cohn, Rachel; Thakar, Ketan; Lowe, Andre et al. (2018) A Contraction Stress Model of Hypertrophic Cardiomyopathy due to Sarcomere Mutations. Stem Cell Reports :
Chopra, Anant; Kutys, Matthew L; Zhang, Kehan et al. (2018) Force Generation via ?-Cardiac Myosin, Titin, and ?-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions. Dev Cell 44:87-96.e5
DeLaughter, Daniel M; Bick, Alexander G; Wakimoto, Hiroko et al. (2016) Single-Cell Resolution of Temporal Gene Expression during Heart Development. Dev Cell 39:480-490
Hinson, J Travis; Chopra, Anant; Lowe, Andre et al. (2016) Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis. Cell Rep 17:3292-3304
Hinson, John T; Chopra, Anant; Nafissi, Navid et al. (2015) HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349:982-6