This Program Project Grant application describes studies we plan to perform as a continuation of our? previous projects concerned with the regulation of cardiovascular function, primarily by endothelium-derived? mediators, nitric oxide and reactive oxygen species. The present application builds on our previously? obtained data to further establish the role of these agents in the control of vascular and cardiac function. Our? overall hypothesis that we aim to test is that oxygen radical species, derived through activation of Nox? oxidases in the vessel wall, by causing a reduction in nitric oxide bioavailability, hasten the development of? vascular dysfunction leading to disease. In the first Project, Dr. Wolin will characterize how Nox-linked signaling? mechanisms affect vascular function and how these mechanisms are altered in pathophysiologic conditions.? In the second Project, Dr. Hintze will examine in mice, rats and dogs the role of NADPH oxidase in the increased? oxidant production secondary to sodium restriction, a state associated with increased angiotensin? production. He will also determine in the dog heart the effects of sodium restriction on NO dependent? regulation of the coronary circulation as well as the fate of substrates and the alteration in the expression of? metabolic enzymes. In the third Project, Dr. Kaley plans to study the effects of aging on vascular function in type 2? diabetic (db/db) and eNOS-KO mice, two different models of metabolic syndrome, each of which is? characterized by increased oxidant stress and a reduction in nitric oxide bioavailability. The projects will be? supported by three cores; one led by Dr. Edwards, providing genotyping of and physiologic measurements in? mice, one led by Dr. Ungvari who will provide expertise in imaging ROS in vessels and tissues by state of the? art methods and one led by Dr.
Oj aimi, who will interpret data obtained by gene array techniques. We? believe that our research will provide conceptual advances that will likely lead to a better understanding of? the development of vascular dysfunction in disease states as well as to novel therapeutic options.?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL043023-16A1
Application #
7248885
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Goldman, Stephen
Project Start
1997-07-01
Project End
2012-03-31
Budget Start
2007-04-09
Budget End
2008-03-31
Support Year
16
Fiscal Year
2007
Total Cost
$1,821,822
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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