Roughly, 25.8 million individuals in the United States (8.3% of the population) suffer from diabetes mellitus, making diabetes mellitus one of the world's fastest growing diseases. For many diabetic patients, cardiovascular complications, such as diabetic cardiomyopathy contribute to the poor prognosis and increasing healthcare costs. The mitochondrion has been identified as playing a role in the development of diabetic cardiomyopathy and the advancement of strategies aimed at protecting the diabetic heart are crucial. Currently a gap in knowledge exists regarding identification of a therapeutic paradigm to rectify mitochondrial dysfunction and contractile abnormalities in the type 2 diabetic heart. My long-term goal is to identify mechanisms and alleviate adverse cardiac effects associated with diabetes mellitus through the manipulation of a single protein target, mitochondrial heat shock protein 70 (mtHsp70), in both type 2 diabetic mice and human patient cardiomyocytes. The objectives of this application are: (1) to determine the effect of mtHsp70 overexpression on cardiac mitochondrial proteome derangement, protein import and protein refolding, ultimately impacting cardiac function and (2) to evaluate the therapeutic potential of mtHsp70 overexpression in type 2 diabetic human patient cardiac tissue. My central hypothesis is that the cardiac dysfunction and mitochondrial proteome derangement observed during type 2 diabetes mellitus will be rectified by manipulation of the mitochondrial protein import process. This work is innovative conceptually because it uses the manipulation of the mitochondrial protein import system to restore cardiac function in the diabetic heart. Further, the use of a novel heart specific mtHsp70 overexpressor, db/db mouse model makes this work methodologically innovative. The expected outcomes will provide insight into the impact of type 2 diabetes mellitus on mitochondrial proteome derangement, and the rectification of mitochondrial dysfunction by manipulation of a single protein target, mtHsp70, advancing the knowledge of cardiac abnormalities seen in the type 2 diabetic heart. Evaluation of the type 2 diabetic human heart will provide a translational link between mechanisms contributing to disease progression and clinical manifestations in diabetic patients improving cardiovascular health and thus decrease the incidence of death from cardiovascular complications associated with diabetes mellitus.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2014 → 06/30/2015|