This project has three principal goals: 1. The recognition of the role that stem cell surface antigens have in conditioning the growth and differentiation of cardiac stem cells (CSCs) in myocardial cell lineages; 2. The demonstration that age leads to a downregulation of the hepatocyte growth factor (HGF)-cMet and insulin-like growth factor-1 (IGF-1)-IGF-1 receptor (IGF-1R) systems, and to an upregulation of the renin-angiotensin system (RAS) in CSCs and early committed cells; and 3. The identification of an age-dependent increase in the local RAS, which mediates the formation of reactive oxygen species (ROS), triggering apoptotic and necrotic death of CSCs, progenitors and precursors. Point 1 aims at the characterization of the classes of CSCs regulating the physiologic turnover of myocardial cells in the adult normal heart. This information is considered critical for the elucidation of the potential mechanisms of cardiac repair in disease states. Point 2 raises the possibility that attenuation of the HGF-c-Met system with age negatively interferes with the migration of CSCs from the storage areas to the injured sites of ventricular myocardium, limiting their activation and growth. Reduction of cell turnover results in accumulation of old cardiac cells with defective function. Similarly, the IGF-I-IGF-I R system might be downregulated in aging CSCs and this could affect cell replication, differentiation and survival, contributing to the development of the aging myopathy. Point 3 emphasizes the effects of oxidative damage induced by an upregulation of the local RAS not adequately counteracted by the IGF-I-IGF-1R system in the old heart. Low levels of oxidative challenge initiate apoptosis and high levels promote necrosis. Death of CSCs and early committed cells may result in the loss of the growth reserve of the aging myocardium. Senescent myocytes, coronary arterioles and capillary structures could die and the architecture of the ventricular wall may assume pathologic characteristics. These might include mural thinning, cavitary dilation, poor tissue perfusion, cardiac dysfunction and, ultimately, terminal failure and death. Thus, the hypothesis is advanced that CSC aging occurs and involves downregulation of growth factor receptor systems favoring locomotion, growth and differentiation. Conversely, inhibitors of the cell cycle and marker of cellular senescence increase in combination with oxidative DNA damage, potentiating the endogenous cell death pathway.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL075480-05
Application #
7394400
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lundberg, Martha
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2008-06-15
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$414,829
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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