Vascular Endothelial Growth Factor Receptor Interactions and Allograft Rejection

血管内皮生长因子受体相互作用和同种异体移植排斥

• 批准号: 8239118
• 负责人: David M. Briscoe
• 金额: $ 49.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-11-17 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239118
• 关键词: Acute; Address; Allografting; Angiogenic Factor; Area; Binding; Biology; Cells; Chemotaxis; Chronic; Clinical; Development; Effector Cell; Endothelial Cells; Evolution; Family; Graft Survival; Humoral Immunities; Immune; Immune response; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Ischemia; Isoantibodies; Knockout Mice; Lead; Life; Ligands; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Molecular; Mononuclear; Neuropilin-1; Neuropilins; Organ Transplantation; Outcome; Oxidative Stress; Physiological; Population; Process; Regulatory T-Lymphocyte; Reperfusion Injury; Reperfusion Therapy; Research; Research Proposals; Role; Semaphorin-3; Semaphorin-3A; Semaphorins; Signal Transduction; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Mice; Translating; Transplantation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular remodeling; allograft rejection; base; cell motility; clinically relevant; cytokine; end-stage organ failure; immunoregulation; in vivo; in vivo Model; inhibitor/antagonist; isoimmunity; migration; novel; novel strategies; novel therapeutics; overexpression; prevent; receptor; response

DESCRIPTION (provided by applicant): This project is based on the observation that Vascular Endothelial Growth Factor (VEGF) is overexpressed within allografts in association with ischemia-reperfusion, humoral immunity and acute and chronic rejection. Current paradigms suggest that it functions as a dominant factor mediating vascular remodeling, especially in association with chronic inflammation. However, VEGF also has potent proinflammatory effects in association with cell-mediated immune inflammation. The novelty of this research proposal relates to recent observations that the VEGF receptors (VEGFR) KDR (VEGFR2), Flt-1 (VEGFR1) and neuropilin family molecules are expressed on populations of effector, memory and FOXP3high T regulatory cells. Further, our ongoing observations indicate that VEGF-KDR interactions are potent to mediate motility and activation responses within T effector cells. Nevertheless, it is not known if VEGF may interact with all T cell subsets, or whether it mediates different responses in different VEGFR-expressing T cells. In this R01, we plan to question the interplay between VEGF and Class 3 semaphorins, and how these molecules interact with their common neuropilin receptors expressed on T effector and T regulatory cells in the alloimmune response. Since VEGF is thought to compete with class 3 semaphorins for binding to the neuropilins, these observations beg the question whether VEGF binding may alter Sema3-inducible inhibitory/regulatory immune responses. Our hypothesis is that intragraft VEGF interacts with circulating VEGFR-expressing T cells, and that individual VEGFRs on T cell subsets elicit signals that either promote or suppress migratory and activation responses. We will test this hypothesis in two specific aims in which we will 1), determine the expression and function of VEGFRs in T cell subsets, and evaluate the interplay between VEGF and class 3 semaphorins for T cell chemotaxis, activation and immunoregulatory responses, and 2), determine the effect of VEGF-neuropilin-semaphorin interactions in vivo in physiological models of allograft rejection. Our proposed studies address novel and clinically relevant questions and our approach provides for cohesiveness to translate in vitro findings into clinically relevant models in vivo. Collectively, the implications and clinical relevance of this area of investigation is that local intragraft VEGF, which is traditionally thought to serve simply as an angiogenesis factor, may be a novel factor that coordinates interactions among circulating VEGFR-expressing T effector and T regulatory cells within the graft. PUBLIC HEALTH RELEVANCE: Organ transplantation is a life saving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. We have identified that Vascular Endothelial Growth Factor (VEGF) facilitates the recruitment and activation of T cells. In this research proposal, we plan to perform mechanistic studies addressing questions about the molecular basis for VEGF receptor interactions in T cells, and how overexpressed VEGF within transplanted organs may result in chronic rejection.

描述（由申请人提供）：该项目基于以下观察：血管内皮生长因子（VEGF）在同种异体移植物中过度表达，与缺血再灌注、体液免疫以及急性和慢性排斥反应相关。目前的范式表明，它作为介导血管重塑的主导因素发挥作用，特别是与慢性炎症相关。然而，VEGF 还具有与细胞介导的免疫炎症相关的有效促炎作用。该研究提案的新颖性与最近观察到 VEGF 受体 (VEGFR) KDR (VEGFR2)、Flt-1 (VEGFR1) 和神经毡蛋白家族分子在效应细胞、记忆细胞和 FOXP3high T 调节细胞群上表达有关。此外，我们持续的观察表明 VEGF-KDR 相互作用能够有效介导 T 效应细胞内的运动和激活反应。然而，尚不清楚 VEGF 是否可能与所有 T 细胞亚群相互作用，或者它是否介导不同表达 VEGFR 的 T 细胞的不同反应。在本 R01 中，我们计划质疑 VEGF 和 3 类信号蛋白之间的相互作用，以及这些分子如何在同种免疫反应中与 T 效应细胞和 T 调节细胞上表达的常见神经毡蛋白受体相互作用。由于 VEGF 被认为与 3 类信号蛋白竞争与神经毡蛋白的结合，因此这些观察结果引出了 VEGF 结合是否可能改变 Sema3 诱导的抑制/调节免疫反应的问题。我们的假设是，移植物内 VEGF 与循环中表达 VEGFR 的 T 细胞相互作用，并且 T 细胞亚群上的单个 VEGFR 会引发促进或抑制迁移和激活反应的信号。我们将在两个具体目标中测试这一假设，其中我们将1）确定T细胞亚群中VEGFR的表达和功能，并评估VEGF和3类信号蛋白之间对T细胞趋化性、激活和免疫调节反应的相互作用，以及2）确定同种异体移植排斥的生理模型中VEGF-神经毡蛋白-信号蛋白体内相互作用的影响。我们提出的研究解决了新的和临床相关的问题，我们的方法提供了将体外研究结果转化为临床相关体内模型的一致性。总的来说，这一研究领域的意义和临床意义在于，传统上认为只是作为血管生成因子的局部移植物内 VEGF 可能是协调移植物内循环表达 VEGFR 的 T 效应细胞和 T 调节细胞之间相互作用的新因子。 公众健康相关性：器官移植对于终末期器官衰竭的个体来说是一种挽救生命的疗法，但所有移植最终都会由于一种称为慢性同种异体移植排斥的过程而失败。我们已经发现血管内皮生长因子 (VEGF) 促进 T 细胞的募集和激活。在这项研究计划中，我们计划进行机制研究，解决有关 T 细胞中 VEGF 受体相互作用的分子基础的问题，以及移植器官内过度表达 VEGF 如何导致慢性排斥反应。