Angiogenesis, formation of new blood vessels from pre-existing vessels is a hallmark of many eye diseases such as age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity and vascular glaucoma, which are among leading cause of visual loss in the USA and throughout the world. Vascular endothelial growth factor (VEGF), the major stimulator of angiogenesis, elicits its effect by binding to and activating two endothelial receptors namely VEGFR-1/FLK-1 and VEGFR-2/FLT-1. Although activation of VEGFR-2 has been demonstrated to be an essential requirement for induction of angiogenesis, the role of VEGFR-1 in angiogenesis is largely unknown. We will investigate the molecular mechanisms responsible for action of VEGFR-1, such as activation of signaling molecules or induction of immediate early genes (IEG) that might drive its anti-angiogenesis effects in endothelial cells. The significance of the results obtained from the proposed study lies in their potential to provide fundamental information on how VEGFR-1 communicates to control/restrain angiogenesis in endothelial cells. The importance of angiogenesis in ocular diseases is well recognized. our long-term goal is to begin to apply the information obtained from this project to the design of strategies to regulate angiogenesis in clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
1R03EY013706-01
Application #
6415729
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
2002-02-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$162,125
Indirect Cost
Name
Boston University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Singh, Amrik J; Meyer, Rosana D; Navruzbekov, Gyulmagomed et al. (2007) A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis. Proc Natl Acad Sci U S A 104:5413-8
Meyer, Rosana D; Qian, Xiaofeng; Guo, Hwai-Chen et al. (2006) Leucine motif-dependent tyrosine autophosphorylation of type III receptor tyrosine kinases. J Biol Chem 281:8620-7
Meyer, Rosana D; Mohammadi, Moosa; Rahimi, Nader (2006) A single amino acid substitution in the activation loop defines the decoy characteristic of VEGFR-1/FLT-1. J Biol Chem 281:867-75
Rahimi, Nader (2006) VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 11:818-29
Rahimi, Nader (2006) Vascular endothelial growth factor receptors: molecular mechanisms of activation and therapeutic potentials. Exp Eye Res 83:1005-16
Singh, Amrik J; Meyer, Rosana D; Band, Hamid et al. (2005) The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation. Mol Biol Cell 16:2106-18
Meyer, Rosana D; Singh, Amrik; Majnoun, Fredric et al. (2004) Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation. Oncogene 23:5523-31
Meyer, Rosana D; Singh, Amrik J; Rahimi, Nader (2004) The carboxyl terminus controls ligand-dependent activation of VEGFR-2 and its signaling. J Biol Chem 279:735-42
Meyer, Rosana D; Latz, Catharina; Rahimi, Nader (2003) Recruitment and activation of phospholipase Cgamma1 by vascular endothelial growth factor receptor-2 are required for tubulogenesis and differentiation of endothelial cells. J Biol Chem 278:16347-55