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：原同种异体移植物排斥是由受体对供体抗原的免疫反应介导的，由活化的 CD4+ T 效应细胞启动和协调。然而，多种途径同时作用以控制和调节免疫反应，并且提出这种免疫调节过程可以预防和抑制效应T细胞的激活和排斥反应。 DepTOR 是最近发现的一种细胞内因子，可调节癌细胞中 mTOR 诱导的信号反应。此外，在内皮细胞中，DepTOR 能够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DepTOR在CD4+ T细胞中高水平表达，并且DepTOR的强制过度表达在体外和体内调节丝裂原诱导的增殖和激活反应。由于 mTOR 信号传导对于 T 效应细胞和 T 调节细胞的激活至关重要，因此我们建议这些观察结果将 DepTOR 确定为重要的细胞内调节剂，有可能决定免疫反应的表型和功能结果。我们的目标是开发和使用新型敲除和转基因小鼠来确定 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 是否调节与同种异体移植排斥相关的 T 细胞激活反应和炎症。我们的假设是，DepTOR 是一种细胞内在分子，可调节 CD4+ T 效应子和调节细胞功能，从而调节细胞介导的同种免疫炎症。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 CD4+ T 细胞中 DepTOR 的表达和细胞内在功能，2) 确定 DepTOR 在同种异体移植排斥中的功能，并评估其在调节同种免疫中的作用体内反应。我们提出的研究解决了基本但与临床相关的问题，并且我们的方法提供了将体外发现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相关性在于，我们的研究结果极有可能将 DepTOR 定义为免疫的关键调节剂，因此表明可以通过关注 DepTOR 相互作用来预防或抑制炎症。由于可以靶向 DepTOR 降解，因此这一结果将具有广泛的临床和治疗意义。