Angiogenesis and Chronic Rejection

血管生成和慢性排斥

• 批准号: 7162969
• 负责人: David M. Briscoe
• 金额: $ 42.62万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162969
• 关键词: Adaptor Signaling Protein; Address; Allografting; Angiogenic Factor; Area; Binding; Binding Sites; Biological; Biological Response Modifiers; Biology; Blood Vessels; Boston; Cells; Chronic; Chronic Disease; Clinic; Complement component C1s; CpG Islands; Cytoplasmic Tail; Development; Dissociation; Dominant-Negative Mutation; Endothelial Cells; Excision; Family; Foundations; Funding; Future; Generations; Genetic Transcription; Growth Factor Overexpression; Human; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammatory Response; Laboratories; Ligation; Link; Lymphocyte; MHC Class II Genes; Mediating; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Molecular Analysis; Numbers; Pathologic Processes; Pathway interactions; Pediatric Hospitals; Process; Production; Productivity; Promoter Regions; Protein Overexpression; Proteins; Reagent; Reporting; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; TNFRSF5 gene; Testing; Time; Trans-Activators; Transact; Transactivation; Transcriptional Activation; Transcriptional Regulation; Transplantation; Universities; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; base; experience; heart allograft; human FRAP1 protein; in vivo; in vivo Model; isoimmunity; mRNA Expression; mTOR Signaling Pathway; novel; programs; promoter; response; therapeutic angiogenesis; tool

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.

描述（由申请人提供）：血管生成，即从既存血管生成新血管，是许多病理过程的组成部分，其特征与细胞介导的免疫炎症相关。然而，令人惊讶的是，很少有关于免疫应答导致血管生成因子表达的机制和血管生成在同种免疫中的作用的报道。在R 01 AI 46756的前一个资助期，我们开始分析淋巴细胞诱导的血管生成的分子基础，并确定了CD 40 L-CD 40相互作用介导强效血管生成因子血管内皮生长因子（VEGF）的转录激活。此外，我们发现CD 40 L诱导的VEGF表达对体内血管生成的发展具有功能性;并且VEGF在同种异体移植物排斥反应中表达，并与同种异体移植物排斥反应相关。我们的总体假设是，血管内皮细胞（EC）中的CD 40信号转导代表了同种免疫反应和VEGF表达之间的机制联系。在这个竞争性的更新应用程序中，我们试图把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，我们计划探讨体内慢性同种异体移植排斥反应中VEGF过度表达的后果的基本问题。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Mukhopadhyay博士实验室进行，一个在马约诊所的Mukhopadhyay博士实验室进行。我们的具体目标是：1）鉴定在EC中介导CD 40诱导的VEGF表达的TNFR相关因子（TRAP）衔接蛋白，2）确定mTOR在EC中CD 40诱导的VEGF表达中的作用，3）确定EC中CD 40诱导的VEGF反式激活的机制;和4）确定VEGF在体内慢性同种异体移植排斥反应起始中的功能。总之，我们相信这一建议是集中的，并可能导致重要的信息移植血管生物学。此外，这些研究的结果也应该提供了基础的识别新的目标，用于抑制免疫介导的血管生成的治疗重要性，在许多慢性疾病，包括慢性同种异体移植排斥反应。