Angiogenesis and Chronic Rejection

血管生成，即从先前存在的血管生成新血管，是许多病理性疾病的组成部分。 过程，并且特征性地与细胞介导的免疫炎症相关。然而，令人惊讶的是， 关于免疫应答导致表达 血管生成因子和血管生成在同种免疫中的作用。在R 01 AI 46756的上一个资助期， 我们开始分析淋巴细胞诱导血管生成的分子基础， CD 40 L-CD 40相互作用介导强效血管生成因子Vascular的转录激活 内皮生长因子（VEGF）。此外，我们发现CD 40 L诱导的VEGF表达是功能性的， 体内血管生成的发展;以及VEGF在同种异体移植物中表达，并与同种异体移植物相关 排斥反应我们的总体假设是，血管内皮细胞（EC）中的CD 40信号转导代表了一种免疫应答。 同种免疫反应和VEGF表达之间的机制联系。在这次竞争性续约申请中， 我们试图将我们的机制问题集中在EC中介导VEGF表达的CD 40信号通路上。 并且，我们计划探索关于VEGF过度表达对慢性胰腺炎的后果的基本问题。 体内同种异体移植排斥反应。我们已经计划了四个具体的目标，其中三个将在Dr. D.C.科的 一个在波士顿儿童医院的实验室，一个在马约诊所的Mukhopadhyay博士的实验室。我们 特异性目的将1）鉴定TNFR相关因子（TRAP）衔接蛋白，其介导CD 40诱导的肿瘤坏死因子受体活化。 2）确定mTOR在EC中CD 40诱导的VEGF表达中的作用，3）确定mTOR在EC中CD 40诱导的VEGF表达中的作用， CD 40诱导EC中VEGF反式激活的机制;和4）确定VEGF在EC中的功能 体内慢性同种异体移植排斥反应的开始。我们共同认为，这一提议是有重点的， 产生对移植血管生物学重要的重要信息。此外，这些研究的结果 还应该为鉴定用于抑制免疫介导的免疫缺陷的新靶点提供基础。 血管生成在包括慢性同种异体移植排斥在内的许多慢性疾病中具有治疗重要性

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