Angiogenesis, the sprouting of new blood vessels from pre-existing ones is crucial for normal biological processes, including embryogenesis, reproduction, and wound healing. Formation of functional blood vessels entails proliferation, survival, migration, and differentiation of endothelial cells to form a vascular network in response to soluble growth factors and extra-cellular matrix. Ras, the proto-oncogene is a prominent signal transducer and accepts input signals from various types of receptors including the receptors for Vascular Endothelial Growth Factor, a key angiogenic molecule. Activation of Ras along with its regulation is important for maintaining proper endothelial cell function and hence angiogenesis. Activated Ras induces proliferation of endothelial cells in vivo leading to gross malfunctioning of the endothelium resulting in mice death. However the mechanistic basis of these defects remains to be established. The basic goal of this project is to investigate the relationship between Ras signal transduction and angiogenesis both in vitro and in vivo. In Specific Aim 1 we will determine how Ras activation affects vascular function in vivo with the help of an inducible endothelial specific expression of an activated Ras transgene. In Specific Aim 2 low copy number inducible vectors expressing various effector domain mutants of activated H-Ras will be used to explore the contributions of downstream signaling components in regulating endothelial cell proliferation, survival, and vascular differentiation. In Specific Aim 3 we will study the effects of stably expressing activated forms of various Ras isoforms using low copy number inducible vectors on various angiogenic phenotypes and signaling pathways.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2008 → 06/30/2010|