Role of T cell Specific Adaptor Protein in Alloimmunity

T 细胞特异性衔接蛋白在同种免疫中的作用

• 批准号: 8190975
• 负责人: David M. Briscoe
• 金额: $ 21.71万
• 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: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190975
• 关键词: Adaptor Signaling Protein; Adaptor Signaling Protein Gene; Address; Age; Alloantigen; Allografting; Antigens; Autoimmune Diseases; B-Lymphocytes; Biological; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular Immunity; Chronic; Clinical; Complex; Defect; Development; Exploratory/Developmental Grant; Future; Generations; Goals; Graft Rejection; Graft Survival; IL2RA gene; Immune response; Immunity; Individual; Inflammation; Inflammatory; Injury; Interleukin-2; Interleukin-4; Investigation; Knock-out; Knockout Mice; Lead; Learning; Life; Mediating; Mitogens; Modeling; Mus; Organ Transplantation; Outcome; Participant; Pathway interactions; Peripheral; Play; Process; Production; Protein Tyrosine Kinase; RANTES; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Role; Self Tolerance; Signal Transduction; Small Interfering RNA; Stimulus; Stromal Cell-Derived Factor 1; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Transplantation; Transplantation Tolerance; Tyrosine; Vascular Endothelial Cell; adapter protein; allograft rejection; base; cell type; chemokine; clinically relevant; clinically significant; cytokine; end-stage organ failure; heart allograft; immunoregulation; in vivo; isoimmunity; lupus-like; migration; novel; prevent; protein function; response; src Homology Region 2 Domain; therapeutic development

DESCRIPTION (provided by applicant): Allograft rejection is mediated by the recipient's immunological response to donor antigen, initiated and coordinated by CD4+ T cells. Once T cells encounter alloantigen, they undergo expansion and differentiation into effectors and/or memory T cells. Activation also results in the expansion of regulatory T cells that function to control the immune response, and it is proposed that this process of immunoregulation is critical for long term allograft survival. Within T cells, several adapter proteins have been found to play central roles in T cell receptor-induced signal transduction, and several have been found to be active participants in the formation of signaling complexes, which modulate the T cell activation response. T-cell-Specific Adaptor Protein (TSAd) is a SH2 domain containing intracellular adaptor molecule that was initially reported to be restricted in its expression to T cells. Increasing evidence suggests that the function of TSAd in T cells is complex, and that it is of importance in both effector as well as well as regulatory responses. However, no study has addressed questions about the biology of TSAd in allograft rejection and/or in the alloimmune response. This exploratory research proposal is based on novel preliminary observations in which we observed that TSAd knockout recipients of cardiac allografts have a profound defect in alloimmune regulation. The overall goal of our research is to characterize how TSAd mediates immunoregulation following transplantation. Specifically, we plan to use TSAd knockout mice as recipients of allografts to determine its function in the rejection process, to identify its role in the generation and function of alloreactive T cells and to identify putative targets of TSAd activity within alloimmune T regulatory cells. Our hypothesis is that TSAd activity is critical for the generation of alloimmune T regulatory cell function, and further, that the biological effect(s) of TSAd in immunoregulation are mediated via its expression within T cells. We will test this hypothesis in two specific aims in which we will: 1), determine the function of TSAd in allograft rejection, and evaluate its role in regulatory alloimmune responses in vivo, and 2), determine if the functional effect of TSAd in alloimmune regulation is dependent on its expression within T cells. We believe that these studies are ideal for the R21 mechanism, as they will initiate the exploration of a new molecule in the field, and they have significant potential to result in high impact findings. Understanding roles and function(s) for this adaptor in T cells is also likely to be of great clinical importance in transplantation, as they may lead to the identification of targets that shift the immune response from one of immunity/inflammation to one of tolerance. 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. Ongoing research is focused on the understanding of basic mechanisms leading to the development of chronic rejection and mechanisms whereby the alloimmune response causes graft injury. In this research proposal, we plan to determine if an adaptor protein, called TSAd functions in alloimmunity and if we can learn how TSAd-dependent signals can be manipulated in order to achieve long term graft survival in the future.

描述（由申请人提供）：同种异体移植排斥反应由受体对供体抗原的免疫反应介导，由CD 4 + T细胞启动和协调。一旦T细胞遇到同种异体抗原，它们经历扩增和分化成效应和/或记忆T细胞。活化还导致调节性T细胞的扩增，其功能是控制免疫应答，并且提出这种免疫调节过程对于长期同种异体移植物存活是至关重要的。在T细胞内，已经发现几种衔接子蛋白在T细胞受体诱导的信号转导中发挥核心作用，并且已经发现几种衔接子蛋白是信号复合物形成的活性参与者，所述信号复合物调节T细胞活化应答。T细胞特异性衔接蛋白（TSAd）是一种含有SH 2结构域的细胞内衔接分子，最初报道其表达仅限于T细胞。越来越多的证据表明，TSAd在T细胞中的功能是复杂的，并且它在效应反应以及调节反应中都是重要的。然而，没有研究已经解决的问题，生物学的TSAd在同种异体移植排斥反应和/或同种免疫反应。这项探索性的研究建议是基于新的初步观察，我们观察到，TSAd基因敲除受体的心脏同种异体移植物有一个深刻的缺陷，在同种免疫调节。我们研究的总体目标是描述TSAd如何介导移植后的免疫调节。具体而言，我们计划使用TSAd基因敲除小鼠作为同种异体移植物的受体，以确定其在排斥过程中的功能，以确定其在同种异体反应性T细胞的产生和功能中的作用，并确定同种免疫T调节细胞内TSAd活性的推定靶点。我们的假设是TSAd活性对于同种免疫T调节细胞功能的产生是关键的，并且进一步地，TSAd在免疫调节中的生物学效应是通过其在T细胞内的表达介导的。我们将在两个特定目标中检验这一假设，其中我们将：1）确定TSAd在同种异体移植排斥中的功能，并评估其在体内调节同种异体免疫应答中的作用，以及2）确定TSAd在同种异体免疫调节中的功能作用是否依赖于其在T细胞内的表达。我们相信这些研究对于R21机制是理想的，因为它们将启动该领域新分子的探索，并且它们具有产生高影响力发现的巨大潜力。了解这种适配器在T细胞中的作用和功能也可能在移植中具有重要的临床意义，因为它们可能导致识别将免疫应答从免疫/炎症转变为耐受的靶标。 公共卫生相关性：器官移植是终末期器官衰竭患者的一种挽救生命的疗法，但所有移植最终都会因慢性同种异体移植排斥反应而失败。正在进行的研究集中在理解导致慢性排斥反应发展的基本机制和同种免疫反应导致移植物损伤的机制。在这项研究计划中，我们计划确定一种称为TSAd的衔接蛋白是否在同种免疫中发挥作用，以及我们是否可以了解如何操纵TSAd依赖性信号，以便在未来实现长期移植物存活。