Angiogenesis plays a pivotal role in many important disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. VPF/VEGF acts selectively (though not exclusively) on endothelial cells (EC) by means of two high affinity receptor tyrosine kinases Flt-1 and KDR/Flk-1. Both of these receptors are expressed at increased levels by EC during development and in pathophysiological angiogenesis. Since, most of the endothelial cells express both of the receptors and both of them can homodimerize upon binding to VPF/VEGF, therefore it is difficult to comprehend the molecular function of the individual receptor in the presence of the same ligand. The proposed study aims to dissect the functional aspects and sole responsiveness of these receptors for VPF/VEGF mediated signaling in EC. Chimeric receptors of both KDR and Flt-1 and their respective mutants will be utilized to study signaling pathways responsible for KDR and Flt-1 in vascular endothelial cells. The proposed study thus will delineate the individual role of these two receptors in VPF/VEGF-mediated signaling and will also shed new light on the molecular mechanisms of angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA086436-01
Application #
6135361
Study Section
Pathology A Study Section (PTHA)
Program Officer
Lohrey, Nancy
Project Start
2000-03-15
Project End
Budget Start
2000-03-15
Budget End
2001-04-14
Support Year
1
Fiscal Year
2000
Total Cost
$32,416
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215