The primary purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in cardiology. The applicant proposes to acquire additional skills in molecular biology and somatic gene transfer in the context of a project that builds upon his previous experience in studying apoptosis and signal transduction. Cardiomyocyte apoptosis has been documented in many clinically pathways conditions including human and experimental ischemic heart disease. However, the intracellular pathways controlling cardiomyocyte cell death and the functional contribution of apoptosis to cardiac disease pathogenesis, have not been delineated. The goals of this proposal are to understand the role of PI 3-kinase signaling pathways in blocking cardiomyocyte apoptosis and the functional significance of cardiomyocyte apoptosis in an experimental model of ischemic heart disease. Insulin-like growth factor-I (IGF-I) has beneficial effects on both cardiomyocyte function and survival. Binding of IGF-I to its receptor initiates a complex array of signaling events. In many systems, activation of phosphatidylinositol (PI) 3-kinase is critical to the ability of IGF-I to block apoptosis. Recently, the serine-threonine kinase, Akt, has been identified as both necessary and sufficient for the ability of PI 3-kinase to block apoptosis in neurons. This proposal is based on three hypotheses: 1) that apoptosis in myocardium contributes significantly to infarct size and cardiac dysfunction in ischemia-reperfusion (IR), 2) that the benefits of IGF-I treatment in IR are mediated through local inhibition of cardiac apoptosis, and 3) that IGF-I inhibits cardiomyocyte apoptosis through activation of PI 3-kinase and Akt. To test these hypotheses, we will use adenoviral vectors to express wild-type and mutant forms of specific signaling molecules in cardiomyocytes in vitro and in vivo.
In Specific Aim 1, we examine the role of these pathways on cardiomyocyte survival and function in an in vitro model of transient hypoxia.
In Specific Aim 2, we will examine the effects of these molecules on cardiomyocyte apoptosis and function in vivo.
In Specific Aim 3, we will study the role of the same pathways in cardiac apoptosis and function in a rat model of IR. Understanding the role of specific signaling pathways in cardiomyocyte apoptosis and developing approaches to local modulation of these pathways through somatic gene transfer, may provide novel therapeutic approaches for the management of many clinically important disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL004250-05
Application #
6701351
Study Section
Special Emphasis Panel (ZHL1-CSR-K (O1))
Program Officer
Commarato, Michael
Project Start
2000-02-01
Project End
2005-05-31
Budget Start
2004-02-01
Budget End
2005-05-31
Support Year
5
Fiscal Year
2004
Total Cost
$129,907
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Matsui, Takashi; Davidoff, Amy J (2007) Assessment of PI-3 kinase and Akt in ischemic heart diseases in diabetes. Methods Mol Med 139:329-38
Matsui, Takashi; Nagoshi, Tomohisa; Hong, Eun-Gyoung et al. (2006) Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 290:E789-97
Morissette, Michael R; Cook, Stuart A; Foo, ShiYin et al. (2006) Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circ Res 99:15-24
Matsui, Takashi; Rosenzweig, Anthony (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 38:63-71
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
Grazette, Luanda P; Boecker, Wolfgang; Matsui, Takashi et al. (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231-8
Chao, Wei; Matsui, Takashi; Novikov, Mikhail S et al. (2003) Strategic advantages of insulin-like growth factor-I expression for cardioprotection. J Gene Med 5:277-86
Matsui, Takashi; Rosenzweig, Anthony (2003) Targeting ischemic cardiac dysfunction through gene transfer. Curr Atheroscler Rep 5:191-5
Cook, Stuart A; Novikov, Mikhail S; Ahn, Youngkeun et al. (2003) A20 is dynamically regulated in the heart and inhibits the hypertrophic response. Circulation 108:664-7

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