Angiogenesis and Chronic Rejection

描述(申请人提供)：血管生成，即从原有的血管生成新的血管，是许多病理过程的组成部分，与细胞介导的免疫炎症有关。然而，令人惊讶的是，关于免疫反应导致血管生成因子表达的机制以及血管生成在同种异体免疫中的作用，报道很少(S)。在R01 AI46756的上一次资助期间，我们启动了对淋巴细胞诱导血管生成的分子基础的分析，我们发现CD40L-CD40相互作用介导了强大的血管生成因子血管内皮生长因子(VEGF)的转录激活。此外，我们还发现CD40L诱导的血管内皮生长因子的表达在体内血管生成的发展中起作用，并且血管内皮生长因子在同种异体移植排斥反应中表达，并与排斥反应有关。我们的总体假设是，血管内皮细胞(EC)中的CD40信号代表了同种免疫反应和血管内皮生长因子表达之间的机制联系。在这一竞争性更新应用中，我们试图将我们的机制问题集中在EC中介导VEGF表达的CD40信号通路上。此外，我们计划探讨体内血管内皮生长因子过度表达对慢性同种异体移植排斥反应的影响。我们计划了四个具体的目标，其中三个将在波士顿儿童医院的布里斯科博士的实验室进行，一个将在梅奥诊所的穆霍帕迪耶博士的实验室进行。我们的具体目标是：1)确定介导CD_(40)诱导内皮细胞表达血管内皮生长因子的肿瘤坏死因子受体相关因子(TRAP)接头蛋白(S)；2)确定mTOR在CD_(40)诱导内皮细胞表达血管内皮生长因子中的作用；3)确定CD_(40)诱导血管内皮生长因子反式激活的机制(S)；以及4)确定血管内皮生长因子在体内启动同种异体移植慢性排斥反应中的作用。总之，我们相信这项建议是有重点的，并可能导致对移植血管生物学具有重要意义的重要信息。此外，这些研究的结果还应该为确定新的靶点以抑制免疫介导的血管生成奠定基础，这些新靶点在许多慢性疾病包括慢性同种异体移植排斥反应中具有重要的治疗意义。

DESCRIPTION (provided by applicant): 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 is functional 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.