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，即从原有的血管生成新的血管，是许多病理过程的组成部分。 并与细胞介导的免疫炎症有关。然而，令人惊讶的是， 关于免疫反应导致血管紧张素转换酶表达的机制(S)报道甚少。 血管生成因子及其在同种异体免疫中的作用。在上一次R01 AI46756的资助期， 我们启动了对淋巴细胞诱导血管生成的分子基础的分析，我们发现 CD40L-CD40相互作用介导强大的血管生成因子血管的转录激活 血管内皮生长因子(VEGF)。此外，我们还发现CD40L诱导的血管内皮生长因子的表达是有功能的。 在体内血管生成的发展；以及血管内皮生长因子在同种异体移植中的表达和相关 拒绝。我们的总体假设是，血管内皮细胞(EC)中的CD40信号代表一种 同种异体免疫反应和血管内皮生长因子表达之间的机制联系。在这项竞争性续订申请中， 我们试图将我们的机制问题集中在EC中介导血管内皮生长因子表达的CD40信号通路上。 此外，我们计划探讨血管内皮生长因子过度表达对慢性阻塞性肺疾病的影响的基本问题。 体内同种异体排斥反应。我们计划了四个具体目标，其中三个将在布里斯科博士的 一个在波士顿儿童医院的实验室，一个在梅奥诊所的Mukhop adhyay博士的实验室。我们的 特定的目的将：1)鉴定介导CD40诱导的肿瘤坏死因子受体相关因子(TRAP)接头蛋白(S) 血管内皮生长因子在内皮细胞中的表达，2)确定mTOR在CD40诱导的血管内皮细胞表达中的作用，3)确定 CD40诱导内皮细胞反式激活血管内皮生长因子的机制(S)；4)决定血管内皮生长因子在血管内皮细胞中的作用 体内同种异体慢性排斥反应的启动。我们共同认为，这项提议是有重点的，而且很可能 从而获得了对移植血管生物学有重要意义的信息。此外，这些研究的结果 也应该为识别新的免疫介导的抑制靶点提供基础 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重要的治疗作用

项目成果

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

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

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

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

Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo

• DOI: 10.1097/01.tp.0000173650.83320.b1
• 发表时间: 2005-09-27
• 期刊: TRANSPLANTATION
• 影响因子: 6.2
• 作者: Sho, M;Akashi, S;Nakajima, Y
• 通讯作者: Nakajima, Y