Angiogenesis and Chronic Rejection

血管生成和慢性排斥

• 批准号: 8093958
• 负责人: David M. Briscoe
• 金额: $ 33.37万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-30 至 2012-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093958
• 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; Pathologic Processes; Pathway interactions; Pediatric Hospitals; Process; Production; Productivity; Promoter Regions; 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 Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; allograft rejection; angiogenesis; base; experience; heart allograft; human FRAP1 protein; in vivo; in vivo Model; isoimmunity; mRNA Expression; mTOR Signaling Pathway; novel; overexpression; programs; promoter; response; therapeutic angiogenesis; tool

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

血管生成是来自先前存在的血管的新血管的产生，是许多病理学的组成部分 过程，特征与细胞介导的免疫炎症有关。但是，令人惊讶的是 关于免疫反应导致表达的机制几乎没有报道 血管生成因子和血管生成在同种免疫中的作用。在R01 AI46756的上一期资金期间， 我们开始对淋巴细胞诱导的血管生成的分子基础进行分析，并确定了这一点 CD40L-CD40相互作用介导了有效血管生成因子血管的转录激活 内皮生长因子（VEGF）。此外，我们发现CD40L诱导的VEGF表达 为了发展体内血管生成；并且该VEGF在中表达，并且与同种异体移植有关 拒绝。我们的总体假设是，血管内皮细胞（EC）中的CD40信号代表 同种免疫反应与VEGF表达之间的机械联系。在此竞争性更新应用中， 我们试图将机械性问题集中在介导VEGF表达的EC中的CD40信号通路上。 而且，我们计划探讨有关慢性VEGF过表达的后果的基本问题 体内同种异体移植排斥。我们已经计划了四个特定目标，其中三个将在布里斯科博士的 波士顿儿童医院的实验室，以及Mayo诊所Mukhopadhyay博士实验室的实验室。我们的 具体目的1）识别介导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VEGF表达在EC中的作用，3）确定 CD40诱导的EC中VEGF的反式激活的机制； 4）确定VEGF在 体内慢性同种异体移植排斥的启动。我们在一起，我们相信这一建议是专注的，并且很可能 导致对移植血管生物学重要性的重要信息。而且，这些研究的结果 还应为鉴定新靶标的抑制免疫介导的靶标提供基础 包括慢性同种异体移植排斥的许多慢性疾病中治疗重要性的血管生成

项目成果

Differential activation of human T cells to allogeneic endothelial cells, epithelial cells and fibroblasts in vitro.

• DOI: 10.1186/2047-1440-1-4
• 发表时间: 2012-04-24
• 期刊: Transplantation research
• 作者: Samsonov D;Geehan C;Woda CB;Briscoe DM
• 通讯作者: Briscoe DM

The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance.

• DOI: 10.1097/mot.0000000000000373
• 发表时间: 2017-03
• 期刊: Current opinion in organ transplantation
• 影响因子: 2.2
• 作者: Wedel J;Nakayama H;Kochupurakkal NM;Koch J;Klagsbrun M;Bielenberg DR;Briscoe DM
• 通讯作者: Briscoe DM

Cutting edge: Vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production.

• DOI: 10.4049/jimmunol.0900397
• 发表时间: 2010-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Basu A;Hoerning A;Datta D;Edelbauer M;Stack MP;Calzadilla K;Pal S;Briscoe DM
• 通讯作者: Briscoe DM

CD40-induced signaling in human endothelial cells results in mTORC2- and Akt-dependent expression of vascular endothelial growth factor in vitro and in vivo.

• DOI: 10.4049/jimmunol.181.11.8088
• 发表时间: 2008-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Dormond O;Contreras AG;Meijer E;Datta D;Flynn E;Pal S;Briscoe DM
• 通讯作者: Briscoe DM

A rendezvous before rejection: Where do T cells meet transplant antigens?

• DOI: 10.1038/nm0302-220
• 发表时间: 2002-03-01
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Briscoe, DDM;Sayegh, MH
• 通讯作者: Sayegh, MH