Angiogenesis and Chronic Rejection

血管生成，即从已有血管生成新血管，是许多病理学的组成部分 过程并与细胞介导的免疫炎症相关。然而，令人惊讶的是 关于免疫反应导致表达的机制的报道很少 血管生成因子以及血管生成在同种免疫中的作用。在R01 AI46756的前期资助期间， 我们开始分析淋巴细胞诱导的血管生成的分子基础，并确定 CD40L-CD40 相互作用介导强效血管生成因子的转录激活 内皮生长因子（VEGF）。此外，我们发现CD40L诱导的VEGF表达是功能性的 用于体内血管生成的发展； VEGF 在同种异体移植物中表达并与之相关 拒绝。我们的总体假设是血管内皮细胞 (EC) 中的 CD40 信号传导代表了 同种免疫反应和 VEGF 表达之间的机制联系。在这个竞争激烈的续订申请中， 我们寻求将机制问题集中在 EC 中介导 VEGF 表达的 CD40 信号通路上。 并且，我们计划探索有关 VEGF 过度表达对慢性疾病后果的基本问题。 体内同种异体移植排斥。我们计划了四个具体目标，其中三个将在 Briscoe 博士的实验室中实现 波士顿儿童医院的实验室和梅奥诊所 Mukhopadhyay 博士的实验室都有一个实验室。我们的 具体目标将 1) 鉴定介导 CD40 诱导的 TNFR 相关因子 (TRAP) 衔接蛋白 EC 中的 VEGF 表达，2) 确定 mTOR 在 CD40 诱导的 EC 中 VEGF 表达中的作用，3) 确定 EC 中 CD40 诱导 VEGF 反式激活的机制； 4) 确定 VEGF 在 体内慢性同种异体移植排斥的开始。我们共同相信该提案是有针对性的，并且可能会 产生对移植血管生物学具有重要意义的重要信息。此外，这些研究结果 还应该为识别抑制免疫介导的新靶点提供基础 血管生成对许多慢性疾病（包括慢性同种异体移植排斥）具有治疗重要性

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