The Role of Notch Signaling in Experimental Autoimmune Encephalomyelitis (EAE)

Notch 信号传导在实验性自身免疫性脑脊髓炎 (EAE) 中的作用

• 批准号: 7563973
• 负责人: Wassim Elyaman
• 金额: $ 5.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563973
• 关键词: Affect; Antibodies; Antigens; Autoantigens; Autoimmunity; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Chimeric Proteins; Data; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Generations; Goals; Immune; Immune System Diseases; In Vitro; Inflammatory; Intervention; Knock-in Mouse; Lead; Ligands; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Multiple Sclerosis; Mus; Myelin; Neuraxis; Pathway interactions; Peripheral; Play; Reporter; Role; Severities; Signal Transduction; Study models; T-Cell Activation; T-Lymphocyte; Th1 Cells; Therapeutic; Transplantation; cancer immunotherapy; chemokine receptor; in vivo; jagged1 protein; notch protein; novel; novel strategies; protein activation; receptor expression; response; treatment effect

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and maturation. EAE is used as a model for the study of multiple sclerosis (MS). In this model, antigen-specific CD4+ Th1 cells mediate inflammatory damage in the central nervous system (CNS). A growing body of evidence suggests that Notch signaling plays an integral role in the peripheral maturation of CD4+ T cells. Examination of the role of Notch in murine antigen specific autoimmune encephalomyelitis has led us to the observation that Notch signaling is involved in the initiation of the disease in a ligand-dependent manner and that Jaggedl and Jagged2 play an immuno-regulatory role in the periphery. This proposal outlines molecular and cellular methods for studying the role of Notch signaling in encephalomyelitis. The major goal of this project is to identify and characterize Notch ligand(s) involvement in tolerance. This project will lead to the use of fusion proteins and monoclonal antibody therapy approaches to investigate tolerance strategies in vivo. Therapeutic opportunities that could arise from the manipulation of Notch signaling in immune disorders such as autoimmunity, cancer immunotherapy and transplantation, may prove to be a novel approach to suppress aberrant immune activation.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）由自身抗原特异性T细胞介导，依赖于关键的共刺激信号，使其完全激活和成熟。EAE被用作研究多发性硬化（MS）的模型。在该模型中，抗原特异性CD4+ Th1细胞介导中枢神经系统（CNS）中的炎性损伤。越来越多的证据表明，Notch信号传导在CD4+ T细胞的外周成熟中起着不可或缺的作用。对Notch在鼠抗原特异性自身免疫性脑脊髓炎中的作用的检查使我们观察到Notch信号传导以配体依赖性方式参与疾病的起始，并且锯齿蛋白1和锯齿蛋白2在外周中起免疫调节作用。该提案概述了研究Notch信号在脑脊髓炎中作用的分子和细胞方法。该项目的主要目标是鉴定和表征参与耐受性的Notch配体。该项目将导致使用融合蛋白和单克隆抗体治疗方法来研究体内耐受策略。在自身免疫、癌症免疫治疗和移植等免疫疾病中，Notch信号转导的调控可能带来治疗机会，这可能是抑制异常免疫激活的新方法。