Type II diabetes (T2D) is a growing pandemic and one ofthe most serious health threats of our time. In addition to the well-characterized central endocrine defects, some T2D patients present with distinct manifestation of cardiomyopathy, termed diabetic cardiomyopathy. Diabetic cardiomyopathy occurs in the presence of neither clinically identifiable coronary artery disease nor hypertension, suggesting that independent of its vascular effects, T2D has direct impact on the myocardium. Although its etiology is complex, hyperglycemia and dyslipidemla, leading to increased oxidative stress, may play a central role in the pathogenesis of diabetic cardiomyopathy. Recent studies have proposed that stem cell dysfunction may be responsible for complications related to T2D. The mammalian heart contains a cardiac stem cell (CSC) population with the capacity to maintain and regenerate myocardium. However, little is known about CSCs function in the diabetic heart or their involvement in pathogenesis of diabetic cardiomyopathy. Our preliminary data indicate that the growth and differentiation characteristics of CSCs are impaired in diabetes. We hypothesize that T2D alters CSC growth and differentiation, and these changes in stem cell function contribute to structural abnormalities and contractile dysfunction in the diabetic heart. To test this hypothesis we will: 1) Identify central defects in CSC biology in the diabetic heart in vivo;2) Elucidate the cellular defects provoked by diabetes and nutrient excess in CSCs in vitro;and 3) Rescue the CSCs'functional defects in the diabetic heart in vivo. The studies proposed here will 1) Establish correlation between CSC dysfunction and cardiac abnormalities in the diabetic heart;2) Explore mechanisms by which diabetes and nutrient excess affect function of CSCs;and 3) Decipher whether or not CSC dysfunction significantly contributes to the pathogenesis of diabetic cardiomyopathy using an innovative transgenic mouse model. Results of this study will lead to a better understanding of how diabetes affects CSC competence and function and how these abnormalities contribute to diabetic cardiomyopathy. Successful completion of these studies could illuminate new avenues for preventing or treating T2D.

Public Health Relevance

Type II diabetes is a growing pandemic. Independent of its vascular effects, diabetes directly affects the heart. In this study, we will investigate the influence of diabetes on cardiac stem cells. Successful completion of these studies could lead to development of novel therapeutic approaches targeting cardiac stem cells for preventing or treating cardiac dysfunction in patients with diabetes.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
5P20GM103492-07
Application #
8711513
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
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