Role of Negative Regulation in Development of Diabetes

负面调节在糖尿病发展中的作用

• 批准号: 6575812
• 负责人: JAIME F. MODIANO
• 金额: $ 35.12万
• 依托单位: AMC CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575812
• 关键词: NOD mouse; SCID mouse; T cell receptor; T lymphocyte; biological signal transduction; cell cell interaction; cell cycle; cell growth regulation; cell proliferation; confocal scanning microscopy; gel mobility shift assay; insulin dependent diabetes mellitus; leukocyte activation /transformation; major histocompatibility complex; pancreatic islet transplantation; pathologic process; protein localization; protein structure function; western blottings

DESCRIPTION (provided by applicant): Recent evidence indicates that survival of naive peripheral T cells is an active process requiring the interaction of the T cell receptor with self-peptides presented by the same MHC molecules that are responsible for thymic selection. However this T cell receptor interaction with self MHC does not lead to T cell activation because this process is dampened by a family of negative regulators of activation. Recent work from our group indicates that faulty negative regulation may permit the activation of autoreactive T cells, and that intrinsic hyporesponsiveness of T cell receptor signaling in autoimmune prone animals may further enhance any deficiency in negative regulation. Together, these conditions can lead to enrichment of peripheral autoreactive T cells and ultimately instigate autoimmune disease. This application will reinforce a collaboration between two laboratories with expertise in cell cycle regulation and the immunbiology of Type I diabetes. The experiments proposed are designed to test the hypotheses that (1) failure of negative regulation leads to abortive cell cycle entry and death unless the T cells receive a strong survival signal and (2) because of an intrinsic hyporesponsiveness in T cell receptor signaling the failure of negative regulation preferentially permits the expansion of autoreactive clones resulting in autoimmunity.

描述（由申请人提供）： 最近的证据表明，初始外周 T 细胞的存活是一个活跃的过程，需要 T 细胞受体与负责胸腺选择的相同 MHC 分子呈现的自身肽相互作用。然而，这种 T 细胞受体与自身 MHC 的相互作用不会导致 T 细胞激活，因为这一过程受到一系列激活负调节因子的抑制。我们小组最近的工作表明，错误的负调节可能会导致自身反应性 T 细胞的激活，而自身免疫倾向动物中 T 细胞受体信号传导的内在低反应性可能会进一步加剧负调节的任何缺陷。这些条件共同导致外周自身反应性 T 细胞富集，最终引发自身免疫性疾病。该应用将加强两个在细胞周期调节和 I 型糖尿病免疫生物学方面拥有专业知识的实验室之间的合作。所提出的实验旨在测试以下假设：(1) 负调节失败会导致细胞周期进入失败和死亡，除非 T 细胞接收到强烈的生存信号；(2) 由于 T 细胞受体信号的固有低反应性，负调节失败优先允许自身反应性克隆的扩增，从而导致自身免疫。