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.

产品说明：前同种异体移植物排斥是由受体对供体抗原的免疫应答介导的，由活化的CD4+ T效应细胞启动和协调。然而，多种途径同时起作用以控制和调节免疫应答，并且提出这种免疫调节过程用于预防和抑制T效应细胞活化和排斥反应。DepTOR是最近发现的调节癌细胞中mTOR诱导的信号应答的细胞内因子。此外，在内皮细胞中，DepTOR能够有效调节其他细胞内信号传导网络，包括MAPK和STAT诱导的应答。在初步研究中，我们已经发现DepTOR在CD4+ T细胞中以高水平表达，并且DepTOR的强制过表达在体外和体内调节有丝分裂原诱导的增殖和活化应答。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，我们建议这些观察将DepTOR鉴定为重要的细胞内调节剂，其具有决定免疫应答的表型和功能结果的潜力。我们的目标是开发和使用新型基因敲除和转基因小鼠，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是否调节与同种异体移植排斥相关的T细胞活化反应和炎症。我们的假设是DepTOR是一种调节CD4+ T效应细胞和调节细胞功能的细胞内在分子，从而调节细胞介导的和同种免疫炎症。我们将在两个特定的目标中测试这一假设，其中我们将1）确定DepTOR在CD4+ T细胞中的表达和细胞内在功能，以及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应答中的作用。我们提出的研究解决了基本但临床相关的问题，我们的方法提供了凝聚力，将体外研究结果转化为体内临床相关模型。总的来说，这一研究领域的意义和相关性在于，我们的发现具有将DepTOR定义为免疫的关键调节剂的高潜力，因此将表明通过关注DepTOR相互作用来预防或抑制炎症是可能的。由于靶向DepTOR降解是可能的，因此该结果将具有广泛的临床和治疗意义。