Function of DepTOR in T Cell Activation and Alloimmunity

DepTOR 在 T 细胞激活和同种免疫中的作用

• 批准号: 8785808
• 负责人: David M. Briscoe
• 金额: $ 21.98万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785808
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Adipose tissue; Antigens; Applications Grants; Area; Binding; Biological; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Collaborations; Development; Doxycycline; Effector Cell; Employee Strikes; Endothelial Cells; Eragrostis; Future; Homeostasis; Immune response; Immunity; In Vitro; Individual; Inflammation; Intrinsic factor; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; MAP Kinase Gene; Mediating; Mitogens; Mus; Muscle Cells; Organ Transplantation; Outcome; Pathway interactions; Pattern; Phenotype; Population; Process; Reaction; Reagent; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Resolution; Resources; Role; STAT1 gene; Signal Transduction; Splenocyte; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translating; Transplantation; Ubiquitination; allograft rejection; cancer cell; cell type; clinically relevant; end-stage organ failure; functional outcomes; genetic regulatory protein; human FRAP1 protein; immunoregulation; in vivo; in vivo Model; isoimmunity; novel; overexpression; prevent; public health relevance; response; therapeutic development

DESCRIPTION: Pro Allograft rejection is mediated by the recipient's immunological response to donor antigen, initiated and coordinated by activated CD4+ T effector cells. However, multiple pathways operate co-incidentally in order to control and regulate the immune response, and it is proposed that this process of immunoregulation serves to both prevent and restrain T effector cell activation and the rejection reaction. DepTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced signaling responses in cancer cells. Furthermore, in endothelial cells, DepTOR is potent to regulate additional intracellular signaling networks including MAPK and STAT induced responses. In preliminary studies, we have found that DepTOR is expressed at high levels in CD4+ T cells, and that forced overexpression of DepTOR modulates mitogen- induced proliferative and activation responses in vitro and in vivo. Since mTOR signaling is of critical importance for the activation of both T effectors and T regulatory cells, we suggest that these observations identify DepTOR as an important intracellular modulator with potential to dictate the phenotypic and functional outcome of an immune response. Our objectives are to develop and use novel knockout and transgenic mice to determine the mechanism of function of DepTOR in CD4+ T cells including T effectors and T regulatory cells, and to determine whether DepTOR modulates T cell activation responses and inflammation in association with allograft rejection. Our hypothesis is that DepTOR is a cell intrinsic molecule that modulates CD4+ T effector and regulatory cell function, and thus cell-mediated and alloimmune inflammation. We will test this hypothesis in two specific aims in which we will 1), determine the expression and cell intrinsic function of DepTOR in CD4+ T cells, and 2), determine the function of DepTOR in allograft rejection, and evaluate its role in regulatory alloimmune responses in vivo. Our proposed studies address fundamental but clinically relevant questions, and our approach provides for cohesiveness to translate in vitro findings into clinically relevant models in vivo. Collectively, the implications and relevance of this area of investigation is that our findings hav high potential to define DepTOR as a key modulator of immunity, and will thus indicate that it is possible to prevent or inhibit inflammation by focusing on DepTOR interactions. Since it is possible to target DepTOR degradation, this outcome will have broad clinical and therapeutic implications.

描述：同种异体前排斥反应是由受体对供体抗原的免疫反应介导的，由活化的CD4+ T效应细胞发起和协调。然而，为了控制和调节免疫反应，多种途径同时起作用，并且提出这种免疫调节过程既可以预防和抑制T效应细胞的活化和排斥反应。DepTOR是最近发现的一种细胞内在因子，可调节mtor诱导的癌细胞信号反应。此外，在内皮细胞中，DepTOR还能有效调节其他细胞内信号网络，包括MAPK和STAT诱导的反应。在初步研究中，我们发现在CD4+ T细胞中，DepTOR高水平表达，并且在体外和体内，强迫DepTOR过表达可调节丝裂原诱导的增殖和激活反应。由于mTOR信号对于T效应细胞和T调节细胞的激活至关重要，我们认为这些观察结果确定了DepTOR是一个重要的细胞内调节剂，具有决定免疫反应表型和功能结果的潜力。我们的目标是开发和使用新的敲除和转基因小鼠，以确定DepTOR在CD4+ T细胞（包括T效应细胞和T调节细胞）中的功能机制，并确定DepTOR是否调节T细胞激活反应和与异体移植排斥相关的炎症。我们的假设是，DepTOR是一种细胞固有分子，可调节CD4+ T效应和调节细胞功能，从而介导细胞介导和同种免疫炎症。我们将在两个特定目标中验证这一假设：1)确定DepTOR在CD4+ T细胞中的表达和细胞内在功能；2)确定DepTOR在同种异体移植排斥反应中的功能，并评估其在体内调节同种异体免疫反应中的作用。我们提出的研究解决了基础但临床相关的问题，我们的方法提供了将体外研究结果转化为体内临床相关模型的凝聚力。总的来说，这一研究领域的意义和相关性在于，我们的发现很有可能将DepTOR定义为免疫的关键调节剂，从而表明通过关注DepTOR的相互作用来预防或抑制炎症是可能的。由于可以靶向detor降解，因此这一结果将具有广泛的临床和治疗意义。