Angiogenesis, the generation of new blood vessels from pre-existing ones, is a component of many pathologic processes and is characteristically associated with cell-mediated immune inflammation. However, surprisingly little has been reported on the mechanism(s) by which the immune response results in the expression of angiogenesis factors and the role of angiogenesis in alloimmunity. In the previous funding period of R01 AI46756, we initiated an analysis of the molecular basis for lymphocyte-induced angiogenesis and we identified that CD40L-CD40 interactions mediate the transcriptional activation of the potent angiogenesis factor Vascular Endothelial Growth Factor (VEGF). In addition, we found that CD40L-induced expression of VEGF isfunctional for the development of angiogenesis in vivo;and that VEGF is expressed in, and is associated with allograft rejection. Our overall hypothesis is that that CD40-signaling in vascular endothelial cells (EC) represents a mechanistic link between the alloimmune response and VEGF expression. In this competitive renewal application, we seek to focus our mechanistic questions on CD40 signaling pathways in EC that mediate VEGF expression. And, we plan to explore basic questions regarding the consequence of overexpression of VEGF for chronic allograft rejection in vivo. We have planned four specific aims, three of which will be performed in Dr Briscoe's laboratory at Children's Hospital Boston, and one in Dr Mukhopadhyay's laboratory at the Mayo Clinic.
Our Specific Aims will 1) identify the TNFR-associated factor (TRAP) adaptor protein(s) that mediate CD40-induced VEGF expression in EC, 2) determine the role of mTOR in CD40-induced VEGF expression in EC, 3) determine the mechanism(s) for CD40-induced trans-activation of VEGF in EC;and 4) determine the function of VEGF in the initiation of chronic allograft rejection in vivo. Together, we believe this proposal to be focused, and will likely result in significant information of importance to transplant vascular biology. Moreover, the results of these studies should also provide the foundation for the identification of novel targets for the inhibition of immune-mediated angiogenesis of therapeutic importance in many chronic diseases including chronic allograft rejection
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