Cardiomyocyte (CM) death has been identified in many clinically important cardiac conditions including heart failure and ischemic injury. Therefore, understanding the signaling pathways that control CM survival may have significant clinical implications. During the first project period, we learned that while acute activation of the serine-threonine kinase, Akt, is cardioprotective, chronic activation of Akt has deleterious effects associated with feedback inhibition of upstream IRS-1/PI 3-kinase (PI3K) signaling. These studies demonstrated the importance of additional PI3K-dependent but Akt-independent cardioprotective effectors. Integrin-linked kinase (ILK), a PI3K-dependent serine-threonine kinase, is one such candidate effector. Interestingly, ILK binds the cytoplasmic tail of p-integrins, raising the possibility that it links biomechanical stress to traditional kinase cascades. Our preliminary data suggest ILK is dynamically regulated in the heart and an important determinant of cardiomyocyte survival. The overall goals of the current proposal are to define the role of ILK in the heart at baseline, and in response to biomechanical and ischemic stress. This proposal is based on three hypotheses: 1) that ILK provides a PI3K-dependent, anti-apoptotic signal in cardiomyocytes (CM), 2) that common signaling mechanisms including ILK control CM survival after both biomechanical and ischemic stress, and that 3) ILK works through both Akt-dependent and -independent downstream pathways. To test these hypotheses, we will utilize mice with conditional, cardiac-specific inactivation of ILK, in combination with somatic gene transfer in models of CM death, ischemic injury, and biomechanical stress.
In Specific Aim 1, we will test, the hypothesis that ILK inhibits CM apoptosis in a PI3K-dependent manner, and define the downstream mechanisms responsible.
In Specific Aim 2, we will generate and characterize cardiac-specific ILK knockout mice.
In Specific Aim 3, we will test the hypothesis that inactivation of ILK in the heart will increase CM apoptosis after aortic banding thereby accelerating the development of heart failure.
In Specific Aim 4, we will test the hypothesis that loss of ILK signaling will increase acute ischemic injury through increased CM apoptosis. Heart failure is a growing cause of morbidity and mortality in the United States. Loss of CMs is cumulative and this likely contributes to the increasing prevalence of heart failure in our aging population. Understanding the role of specific pathways in CM survival may provide novel therapeutic approaches to preventing CM death, thereby preserving cardiac function and reducing the burden of heart failure. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL059521-10A1
Application #
7207322
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
1998-02-01
Project End
2011-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
10
Fiscal Year
2007
Total Cost
$425,000
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Chao, Wei; Shen, Yan; Li, Ling et al. (2005) Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes. Am J Physiol Heart Circ Physiol 289:H2073-80
Aoyama, Takuma; Matsui, Takashi; Novikov, Mikhail et al. (2005) Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652-9
Nagoshi, Tomohisa; Matsui, Takashi; Aoyama, Takuma et al. (2005) PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J Clin Invest 115:2128-38

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