Signaling Mechanisms of Heterotrimeric G proteins

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DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the signaling mechanisms of heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins). The main focus of this application is on the molecular signaling mechanism of G protein Ga13. Ga13 -/- mice died at E9.5. Yet the molecular basis for this embryonic lethality is not clear. Since the yolk sac of Ga13 -/- mouse embryos (at E9.5) did not show any blood vessels, it was postulated that the cause of death was a defective vascularization during embryogenesis. This early embryonic lethality of Ga13 -/- mice makes the study of the role and molecular basis for Ga13 in embryonic angiogenesis difficult. Therefore, we will use tumor angiogenesis as a model to investigate the function of Ga13 in adult angiogenesis in mice in the Specific Aim 1. In the Specific Aim 2, we will explore the molecular mechanism by which Ga13 contributes to adult angiogenesis. G proteins are known as signaling mediators downstream of G protein-coupled receptors. Our recent finding of a critical role for Ga13 in receptor tyrosine kinase-initiated signaling immediately begs the question of how receptor tyrosine kinases signal to Ga13. We will investigate the biochemical and cellular signaling mechanisms by which growth factor receptors transmit the signals to Ga13 in a GPCR-independent manner in the Specific Aim 3. PUBLIC HEALTH RELEVANCE: This research is directly related to human health. Cell migration and angiogenesis are essential for vascular development and tumor growth. Furthermore, effective neovascularization induced by endothelial progenitor cell transplantation for hind limb, myocardial, and cerebral ischemia has been demonstrated in many preclinical studies, and early clinical trials of endothelial progenitor cells transplantation in chronic and acute coronary artery diseases indicate safety and feasibility of cell-based therapies. Therefore, a better understanding of the mechanisms of angiogenesis and of the migration/recruitment of endothelial progenitor cells will advance our combat against cardiovascular diseases and cancers.