The long-term objective of this proposal is to determine how signal relay pathways orchestrate the diverse cellular response that constitutes the angiogenic program. The objective of this proposal is to determine the mechanism by which PLC gamma induces vessel regression. Our current understanding of vessel regression/destabilization suggests 2 scenarios by which PLCg operates. In the first one, PLCg induces expression of cellular factors such as angiopoetin 2 (Ang2) that induce vessel destabilization/regression. In the second one, PLCg antagonizes pro-survival pathways such as the PI3K/Akt pathway and thereby increases apoptosis and vessel regression. The central hypothesis of this proposal is that PLCg increases vessel destabilization and regression by either increasing the levels of regression factors and/or antagonizing pro-survival signaling pathways. My laboratory has made important contributions to our understanding of how PI3K and PLCg drive cellular responses, and in the process we have gained the necessary expertise and tools for all of the proposed experiments.
The aims are listed below. 1. To determine if PLCg promotes the secretion of factors that induce vessel regression. The working hypothesis for this aim is that PLCg increases the expression and secretion of soluble factors such as Ang2 that lead to destabilization and regression of existing vessels. We will determine if a regression factor is secreted, the relative contribution of Ang2 to this activity, and if the quantity of the regression factor is regulated by PLCg. These experiments will directly assess the possibility that PLCg acts through a regression factor such as Ang2 to drive the destabilization/regression of vessels. 2. To determine if PLCg induces vessel regression by antagonizing PI3K. The working hypothesis for this aim is that PLCg competes with PI3K for its substrate phosphoinositide 4,5 P2, and thereby suppress the PI3K/Akt pathway that is essential for vessel stability. We will use our well-characterized panel of signaling mutants to compare the output of the PI3K/Akt pathway under conditions when PLCg is or is not activated. In addition, we will test if engaging the Akt (which is downstream of PI3K) prevents vessel regression. These experiments will determine if PLCg is promoting vessel regression by antagonizing the """"""""positive"""""""" PI3K/Akt pathway. The proposed studies are highly innovative for two reasons. First, the approach of studying signaling enzymes to understand the coordination of cellular responses is a fresh strategy. Second, the idea that PLCg is responsible for promoting vessel regression is a novel and unexplored concept. This proposal is """"""""high impact"""""""" because the resulting information is likely to substantially advance both our basic understanding of how angiogenesis is regulated, and to provide new therapeutic targets for several major, blinding diseases. ? ?
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