血管生成和慢性排斥反应-猫眼课题宝

血管生成和慢性排斥反应

批准号：

7338690

负责人：

David M. Briscoe

金额：

$43.07万

依托单位：

BOSTON CHILDREN'S HOSPITAL

依托单位国家：

美国

项目类别：

财政年份：

2000

资助国家：

美国

项目状态：

已结题

起止时间：

2000-04-01 至 2010-12-31

来源：

https://reporter.nih.gov/project-details/7338690

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

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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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