The process of postnatal neovascularization plays a crucial role in pathogenesis of numerous diseases e.g. diabetic retinopathy, tissue remodeling upon injury, rheumatoid arthritis and tumor growth/metastasis. It has been known that endothelial cells (ECs) and its micro environment is the key for regulation of neovascularization/angiogenesis. However, the signal transduction events underlying this complex process are not well understood. The objective of this proposal is to gain insight the regulatory network in ECs for HIF11 accumulation and neovascularization. Our preliminary genetic analysis of Syk-/+ or Syk-/+;Rac2-/+ mice reveal a requirement of Syk for integrin induced activation of Rac2 and hypoxia induced stabilization of HIF11. We hypothesize that Syk-Vav1-Rac2 signaling axis exists in ECs and plays an obligate role in neovascularization via HIF11 stabilization. Preliminary data from our laboratory also suggest that specific region of Syk (Y342 and Y346 at B linker region, those are cognate binding sites for Vav and PLC3 respectively) appear to be involved in the activation of Rac2 but not Rac1 downstream of integrin signaling and migration. We propose in our Aim1 to determine Syk-Rac2 signaling axis a possible focal point for HIF11 stabilization.
In Aim 2 we propose to evaluate the role of Syk-Rac2 signaling axis in postnatal neovascularization. Considering the importance of postnatal neovascularization, the identification of a novel molecular pathway, Syk-Vav1-Rac2 signaling axis, will result in the development of innovative therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL091385-03
Application #
7844911
Study Section
Special Emphasis Panel (ZRG1-CVS-Q (90))
Program Officer
Gao, Yunling
Project Start
2009-07-06
Project End
2011-06-30
Budget Start
2010-07-06
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$231,750
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Bhat, Vikas; Olmer, Merissa; Joshi, Shweta et al. (2015) Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am J Hematol 90:1027-35
Joshi, Shweta; Singh, Alok R; Zulcic, Muamera et al. (2014) A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1? and HIF2? stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res 12:1520-31
Joshi, Shweta; Singh, Alok R; Zulcic, Muamera et al. (2014) Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS One 9:e95893
Joshi, Shweta; Singh, Alok R; Durden, Donald L (2014) MDM2 regulates hypoxic hypoxia-inducible factor 1? stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem 289:22785-97
De, Pradip; Dey, Nandini; Terakedis, Breanne et al. (2013) An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. Cancer Chemother Pharmacol 71:867-81