? This proposal details a comprehensive 5-year training program for my career development in academic cardiovascular medicine. I have completed clinical training in cardiovascular medicine at Brigham and Women's Hospital and plan to embark on a mentored research program to provide additional scientific training necessary for an independent career in biomedical resesarch. I will gain in-depth experience in cellular biology, genetics, molecular biochemistry, metabolism, and in vivo physiology as applied to the redox regulation of glucose metabolism. Dr. Richard T. Lee will mentor my scientific and career development. Dr. Lee is an internationally recognized leader in the fields of redox regulation, mechano-transduction, and cardiovascular diseases, and has a proven track record for successful career mentorship in academic medicine and the basic sciences. Dr. Evan Rosen of Beth Isreal Deaconess Hospital, an expert in metabolic metabolism and isulin-action, will serve as a co-mentor. In addition, an advisory committee of established medical scientists (Drs. Peter Libby, Thomas Michel) will provide scientific and career advice. The central hypothesis of this proposal is that the ubiquitously expressed redox regulatory protein Txnip (thioredoxin interacting protein) is a key mediator of glucose homeostasis. Txnip expression is highly glucose and insulin responsive. I show that forced Txnip expression significantly attenuates glucose uptake, and targeted Txnip gene deletion in mice promotes glucose uptake and blunts liver glucose production.
My aims are: 1) To explore the mechanisms by which Txnip regulates glucose uptake in a peripheral tissue (fat), using gene deletion and forced overexpression techniques in adipocytes; 2) To test the hypothesis that peripheral glucose uptake is regulated by Txnip expression in fat using mice with fat-selective targeted Txnip gene deletion; and 3) To test the hypothesis that impairment of glucose uptake by oxidative stress is mediated by Txnip using well-defined models of oxidative stress as applied to Txnip gene-deleted mice. Relevance: Diabetes mellitus is an expanding worldwide epidemic that already affects greater than 1 in 15 adults. 4 out of 5 diabetic patients will die prematurely from a cardiovascular cause.
This research aims to understand the fundamental mechanisms of dysregulated sugar metabolism with the ultimate goal of discovering new therapies to prevent or treat this devastating disease and its cardiovascular consequences. (End of Abstract) ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Scott, Jane
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Brigham and Women's Hospital
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Yoshioka, Jun; Chutkow, William A; Lee, Samuel et al. (2012) Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury. J Clin Invest 122:267-79
Chutkow, William A; Lee, Richard T (2011) Thioredoxin regulates adipogenesis through thioredoxin-interacting protein (Txnip) protein stability. J Biol Chem 286:29139-45
Chutkow, William A; Birkenfeld, Andreas L; Brown, Jonathan D et al. (2010) Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity. Diabetes 59:1424-34