Pressure overload-induced cardiac hypertrophy is one of the most common causes of heart failure. Many intracellular signal transduction pathways have been implicated in the development of cardiac hypertrophy and the progression of hypertrophy to heart failure, among which the protein kinase C (PKC) signaling pathway is the focus of this proposal. In preliminary studies, we found that 1) a PKC binding protein, PICOT (PKC-lnteracting Cousin Of Thioredoxin), is up-regulated during the development of cardiac hypertrophy and 2) enforced expression of PICOT in the neonatal rat ventricular myocyte (NRVM) and rat hearts abrogates the development of cardiac hypertrophy. These results suggest that PICOT is a key negative feedback regulator of cardiac hypertrophy, and thus provides a novel strategy to block the development of cardiac hypertrophy and heart failure. The goal of this proposal is to define the molecular mechanism of PKC inhibition by PICOT, and to evaluate the beneficial effects of PICOT overexpression in the rodent models of cardiac hypertrophy and heart failure. We propose the following specific aims: 1) Defining the molecular mechanism of PICOT activity and its interactions with other PKC isoforms, 2) Characterizing the PICOT complex by proteomic approaches, and 3) Defining the physiological consequences of PICOT overexpression in the hearts in vivo. Accomplishing these three specific aims will provide a greater understanding of the negative feedback mechanism of cardiac hypertrophy exerted by inhibiting PKC activity, and will allow for the design of novel therapeutic strategies for the management of cardiac hypertrophy and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080498-05
Application #
7780432
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2006-02-01
Project End
2011-01-30
Budget Start
2010-01-31
Budget End
2011-01-30
Support Year
5
Fiscal Year
2010
Total Cost
$411,461
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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