Cardiac hypertrphy is the most important contributor to cardiovascular morbidity and mortality in westernsocieties. Caridac hypertrophy develops in order to maintain cardiac function against an increasingworkload. Early in the process, this hypertrophic response may be beneficial but sustained hypertrophicactivation ultimately leads to myocardial dysfunction. Interestingly, the intracellular pathways controlling thedevelopment of hypertrophy and which mediate the progression from hypertrophy to heart failure areunclear. Timely activation of humoral factors, such angiotensin II (ANG II) and insulin-like-growth factor-1(IGF-1), delineate the activation processes of specific protein kinases whose integrated responses leads tothe early beneficial cardiac hypertrophy and later to heart failure. IGF-1 administration can inducehypertrophy as well as block cardiac apoptosis; however ANG II can activate both processes. In the heart,activation of phophatidylinositol (PI) 3-kinase is critical to the ability of IGF-1 to block apoptosis. In contrast,the Ras/MAP (mitogen-activated protein) kinase pathway, which can be activated by both IGF-1 and ANG II,has been associated with cardiac hypertrophy. We have found that compensated eccentric cardiachypertrophy is associated with enhanced activation of these kinases; whereby alterations in potassium andcalcium ion channels induced by ANG II and IGF-1 are mainly mediated through MAP kinase and PI 3-kinase activation. The goals of this porposal is to understand the biological roles of specific downstreamsignaling pathways in controlling cardiocyte apoptosis and hypertrophy, and to delineate the contribution ofapoptosis to the development of heart failure. This porposal is based on 3 hypotheses: 1) signalingpathways responsible for the ability of IGF-1 to induce hypertrophy and block apoptosis are distinct; 2)activation of PI 3-kinase accounts for the benefial effects of IGF-1 on cardiocyte survival; and 3) apoptosiscontributes to the development of cardiac dysfunctin in heart failure. To test these hypotheses, we will useadenoviral vectors to express wild-type and mutant-forms of specific signaling molecules in cardiocytes. Thelong term goal is understanding the role of specific signaling pathways in cardiocyte apoptosis anddeveloping approaches to local modulation of these pathways through somatic gene transfer; which mayprovide novel therapeutic appraoches for the management of many clinically important disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
2S06GM008016-36
Application #
7163120
Study Section
Minority Programs Review Committee (MPRC)
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2006-09-25
Budget End
2007-07-31
Support Year
36
Fiscal Year
2006
Total Cost
$216,947
Indirect Cost
Name
Howard University
Department
Type
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
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