Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. VPF/VEGF is the most important angiogenic factor because of its potency and selectivity for vascular endothelium. VPF/VEGF is not only involved in several steps of angiogenesis, but also the only potent factor rendering microvessels hyperpermeable to circulating macromolecules identified so far. VPF/VEGF extensively reprograms gene expression, stimulates endothelial cell migration and division, and protects endothelial cells from apoptosis and senescence. In order to profile the genes induced by VPF/VEGF, DNA microarray assay was conducted with RNA obtained from cultured HUVEC stimulated with VPF/VEGF. Nuclear receptor TR3, a transcription factor, is one of the highly upregulated genes. In addition, Nur77, the mouse homologue of TR3, is upregulated in the mesentery of VPF/VEGF-treated mouse, where only EC express VPF/VEGF receptors. Further experiments indicated that TR3 is required for VPF/VEGF-stimulated HUVEC proliferation. However, overexpression of sense TR3 inhibits VPF/VEGF-stimulated HUVEC migration, but blocking the expression of the endogenous TR3 by an antisense approach triggers HUVEC migration in the absence of VPF/VEGF. It is known that TR3/nur77 plays crucial roles in development, homeostasis and diseases. However, whether TR3/nur77 plays a role in angiogenesis is not known. The overall goal of this application is to study the function of the nuclear receptor TR3/nur77 in VPF/VEGF-induced angiogenesis and the signaling pathways that regulate VPF/VEGF-induced TR3 expression.
The specific aims of this application are: (1) Investigate TR3/nur77 expression in the pathological angiogenesis induced by VPF/VEGF, tumors and wounding. (2) Determine the function of TR3/nur77 in angiogenesis. (3) Define the molecular mechanisms regulating TR3/Nur77 expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA098581-05
Application #
7254772
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2003-07-22
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$155,979
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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