This project will investigate cellular events that lead to the development of left ventricular dysfunction in experimental animals and patients with diabetes mellitus. Diabetes mellitus is associated with a cardiomyopathy characterized in part by impaired diastolic relaxation. In previous animal studies, we have defined biochemical features of this myopathy that suggest that chronic protein kinase C activation and subsequent phosphorylation of the thin filament protein, troponin I, is central to the maladaptation and also that this process can be abrogated by treatment with an AT1 receptor antagonist. The present application will extend these observations. Two parallel lines of investigation are proposed: 1. Studies in diabetic rats and mice will be performed to establish the effects of transcriptional and post-translation modification of thin myofilament proteins on the relaxation properties and contraction kinetics of isolated fibers. These will include troponin I exchange experiments in skinned fibers to establish the functional of significance of TnI phosphorylation and also studies in transgenic mice expressing TnI protein with a mutated PKC site. 2. Studies will be performed on cardiocytes isolated from the myocardium of patients with diabetes in order to establish whether the same biochemical and mechanical abnormalities are present in human heart disease. It is hoped that this pronged approach will allow the extension of a fundamental experimental observation to clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL063704-02S1
Application #
6559402
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$34,232
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Rundell, Veronica L M; Manaves, Vlasios; Martin, Anne F et al. (2005) Impact of beta-myosin heavy chain isoform expression on cross-bridge cycling kinetics. Am J Physiol Heart Circ Physiol 288:H896-903
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