Although the mechanism underlying increased risk of myocardial injury among diabetic patients is not yet clear, it is generally agreed that hyperglycemia contributed to increased risks of myocardial damage during ischemic injury. Mitochondria play a key role in energy production, oxidative stress, and apoptosis in cardiac muscle;alteration of mitochondria function can modulate myocardial function. This proposal will study the role of insulin receptor signaling to mitochondria and define the mechanisms through which insulin receptor signaling modulates mitochondria bioenergetics in normal and diabetic myocardium. Preliminary data have shown that hyperglycemia did not alter myocardial mitochondria function. Rather, insulin deficiency/insulin resistance plays a key role in the regulation of mitochondria function in diabetic myocardium. The proposed experiments will delineated a novel paradigm focused on insulin receptor signaling through Akt translocation to regulate mitochondria bioenergetics in normal and diabetic myocardium. The proposed experiments will identify the mitochondria substrates for insulin receptor signaling and determine whether modulating mitochondria-targeted Akt activation can reverse mitochondrial dysfunction in diabetic myocardium. Since mitochondria plays a key role in cardioprotection, understanding the mechanisms of insulin signal transduction to mitochondria will help design new strategies to prevent exacerbation of myocardial injury in insulin-deficient and insulin- resistant patients.

Public Health Relevance

Diabetes is a significant public health issue and the majority of diabetic patients died of heart disease. Since mitochondria plays a key role in cardioprotection, understanding the mechanisms of insulin signal transduction to mitochondria will help design new strategies to prevent/treat exacerbation of myocardial injury in insulin- deficient and insulin-resistant patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096987-04
Application #
8451308
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2010-04-02
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$354,541
Indirect Cost
$116,541
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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