This proposal is focused on the role of RhoB in vascular and lymphatic angiogenesis. The models used include neonatal retinal neovascularization and skin angiogenesis and lymphangiogenesis. The overall hypothesis of this grant application is that RhoB promotes vascular endothelial phenotypes and inhibits lymphatic differentiation by regulating the transcriptional activity of the transcription factor Db1/Vezf1.
Aim 1 : Determine blood and lymphatic functions that utilize RhoB and Db1/VEZF In this aim we will complete the examination of the retinal vascular and skin vascular and lymphatic phenotypes in RhoB null mice, and rhoB and vezf1 intercrosses. We will also make lymphatic and blood endothelial cells form the intercrossed mice and examine functional effects on proliferation, survival and tube formation.
Aim 2 : Determine the mechanisms of RhoB and Db1/VEZF1 collaboration on gene expression We show evidence that RhoB and Db1 (human homologue of Vezf1) have similar effects on expression of VEGF receptors in endothelial cells and that they collaborate to regulate expression of Nrp1 in particular. We have new data that we can immunoprecipitate the nrp1 promoter with RhoB in a Db1 dependent manner that is when we co-transfect an expression plasmid with wild type Db1 but not Db1 with a point mutation that blocks its interaction with RhoB.
This aim will extend these studies to more fully understand the co-regulation of target genes of RhoB and Db1.
Somewhat surprisingly, our knowledge of lymphatic genetics and molecular biology has lagged significantly behind that of their sister network, the blood vasculature. Our application proposes to study the biology and molecular mechanisms that RhoB and Db1 use to collaborate to regulate retinal angiogenesis and skin angiogenesis and lymphangiogenesis. The disease relevance of these findings could impact both retinal vascular diseases such as diabetic retinopathy and macular degeneration as well as wound healing in multiple settings.
|Kazerounian, Shiva; Gerald, Damien; Huang, Minzhou et al. (2013) RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Cancer Res 73:50-61|
|Gerald, Damien; Adini, Irit; Shechter, Sharon et al. (2013) RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription. Nat Commun 4:2824|
|Bravo-Nuevo, Arturo; Sugimoto, Hikaru; Iyer, Seema et al. (2011) RhoB loss prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice. Am J Pathol 178:245-52|
|Bravo-Nuevo, Arturo; O'Donnell, Rebekah; Rosendahl, Alexander et al. (2011) RhoB deficiency in thymic medullary epithelium leads to early thymic atrophy. Int Immunol 23:593-600|
|Sun, Jingfang; Hopkins, Benjamin D; Tsujikawa, Kaoru et al. (2009) Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina. Am J Physiol Heart Circ Physiol 296:H1344-51|
|Xue, Qi; Nagy, Janice A; Manseau, Eleanor J et al. (2009) Rapamycin inhibition of the Akt/mTOR pathway blocks select stages of VEGF-A164-driven angiogenesis, in part by blocking S6Kinase. Arterioscler Thromb Vasc Biol 29:1172-8|
|Phung, Thuy L; Oble, Darryl A; Jia, Wangcun et al. (2008) Can the wound healing response of human skin be modulated after laser treatment and the effects of exposure extended? Implications on the combined use of the pulsed dye laser and a topical angiogenesis inhibitor for treatment of port wine stain birthmarks Lasers Surg Med 40:1-5|
|Nagy, Janice A; Benjamin, Laura; Zeng, Huiyan et al. (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109-19|
|Takeda, Yoshito; Kazarov, Alexander R; Butterfield, Catherine E et al. (2007) Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 109:1524-32|
|Rao, Sujata; Lobov, Ivan B; Vallance, Jefferson E et al. (2007) Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development 134:4449-58|
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