LYMPHOCYTIC GABAA RECEPTORS

淋巴细胞 GABAA 受体

• 批准号: 6170613
• 负责人: JIDE TIAN
• 金额: $ 10.71万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170613
• 关键词: GABA receptor; NOD mouse; T lymphocyte; apoptosis; biological signal transduction; calcium flux; cytokine; delayed hypersensitivity; gamma aminobutyrate; insulin dependent diabetes mellitus; leukocyte activation /transformation; neuroimmunomodulation; polymerase chain reaction; receptor expression; surface antigens; tissue /cell culture

DESCRIPTION (Applicant's Abstract): T cells express receptors for endogenous neuroactive molecules such as opioids, substance P, and somatostatin which can modulate T cell responses. Gamma-amino butyric acid (GABA) is the major inhibitory neuro-transmitter in the central nervous system. The investigators' preliminary studies have demonstrated that T cells express functional GABA-A receptors. Activation of these GABA-A receptors inhibited T cell proliferation and IL-2 production. Moreover, administration of GABA in vivo inhibited the adoptive transfer of insulin-dependent diabetes mellitus (IDDM) to non obese diabetic (NOD) mice. These preliminary findings suggest that lymphocytic GABA receptors can down-regulate inflammatory processes. This proposal will test the hypothesis that like their neuronal counterparts, lymphocytic GABA receptors are 1) comprised of subunits which are differentially expressed on different T cell populations during development, and that 2) their expression can be regulated by several factors including the activation of T cells, ligands for GABA-A receptors, cytokines, and insulin. The applicant will also test the hypothesis that activation of lymphocytic GABA-A receptors can modulate T cell function, including their cytokine and surface molecule expression, and cytotoxicity. The applicant will characterize the mechanism(s) by which GABA mediated its immuno-modulatory action on T cells. Finally, since GABA inhibited T cell proliferation in vitro and the adoptive transfer of diabetes in vivo , they hypothesize that GABA will inhibit antigen-specific delayed type hypersensitivity (DTH) responses, as well as the spontaneous development of diabetes in NOD mice in vivo. Demonstrating that GABA inhibits Th1-mediated inflammatory responses in vivo could lead to novel approaches for inhibiting T cell-mediated inflammatory process and autoimmune disease. Thus, the results of this proposal will provide basic insights into a new mode of neuro-immunological regulation of T-cells and inflammatory responses. Moreover, the results may have potential clinical application for down-regulating inflammatory processes in man.

描述（申请人的摘要）：T细胞表达受体 内源性神经活性分子，例如阿片类药物，物质P和 生长抑素可以调节T细胞反应。 γ-氨基丁酸 （GABA）是中枢神经中的主要抑制性神经递质 系统。 研究者的初步研究表明 细胞表达功能性GABA-A受体。 这些GABA-A的激活 受体抑制T细胞增殖和IL-2产生。 而且， GABA在体内的管理抑制了 胰岛素依赖性糖尿病（IDDM）至非肥胖糖尿病（NOD）小鼠。 这些初步发现表明淋巴细胞GABA受体可以 下调炎症过程。 该建议将测试 假设像神经元对应物一样，淋巴细胞GABA受体 是1）由在不同的亚基组成的亚基 开发过程中的T细胞群体，以及2）它们的表达可以是 由多种因素调节，包括T细胞的激活，配体 用于GABA-A受体，细胞因子和胰岛素。 申请人也将测试 淋巴细胞GABA-A受体的激活可以调节的假设 T细胞功能，包括其细胞因子和表面分子表达， 和细胞毒性。 申请人将表征其机制 GABA介导了其对T细胞的免疫调节作用。 最后，自加巴以来 在体外抑制T细胞增殖和 糖尿病在体内，他们假设GABA会抑制抗原特异性 延迟类型的高敏性（DTH）反应以及自发性 体内点头小鼠糖尿病的发育。 证明GABA 抑制Th1介导的体内炎症反应可能导致新颖 抑制T细胞介导的炎症过程和 自身免疫性疾病。 因此，该提案的结果将提供基本 洞悉T细胞的神经免疫调节的新模式和 炎症反应。 此外，结果可能具有潜在的临床 申请人类的炎症过程下调。