: While recent years have witnessed an explosion of studies of therapeutic angiogenesis in cardiovascular disease, detailed understanding of regulation of angiogenic response remains an elusive goal. In particular, there is little information regarding events triggering arteriogenesis (growth of mature arteries) and even less data about maturation and preservation of newly formed vessels. Recent studies from our laboratory have identified a novel class of proline/arginine (PR)-rich peptides may function as a """"""""master switch"""""""" in induction of angiogenesis and arteriogenesis in the setting of """"""""inflammatory"""""""" injury and myocardial ischemia. PR39, the prototypical peptide of this class of molecules, is a macrophage-derived protein capable of stimulating development of functional coronary vasculature in mice hearts. The peptide acts by an unusual mechanism, inhibiting proteasome-mediated degradation of a small number of proteins including hypoxia-inducible factor (HIF)- 1I A and NFKB inhibitor IKBA. In addition, PR39 induces expression of FGF signaling proteins FGF receptor I and syndecan-4. This pattern of activity gives PR39 and related peptides the unusual ability to activate both VEGF (via HIF-1A) and FOF signaling thereby placing them at the center of angiogenic/arteriogenic response. In this grant application we propose to study the functional effects of PR39 induced angiogenesis by examining its effects in ameroid coronary constrictor model and hindlimb ischemia model, to define molecular mechanisms of its action by examining in details it interaction with the proteasomes, and to determine the spectrum of its biological activity by examining the pattern of induced gene expression in various angiogenic models. Additional studies will focus on the role vessel survival in long-term maintenance of effective angiogenic/arteriogenic response. It is hoped that this comprehensive assessment of the novel family of angiogenesis """"""""master switch"""""""" genes may shed new light on regulation of arteriogenic response and provide new avenues for development of therapeutic agents for stimulation of vessel growth.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070247-04
Application #
6872177
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$334,339
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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