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（申请人摘要）：T 细胞表达受体 内源性神经活性分子，如阿片类药物、P 物质和 生长抑素可以调节 T 细胞反应。 γ-氨基丁酸 (GABA) 是中枢神经中主要的抑制性神经递质 系统。 研究人员的初步研究表明，T 细胞表达功能性 GABA-A 受体。 激活这些 GABA-A 受体抑制 T 细胞增殖和 IL-2 产生。 而且， GABA 体内给药抑制了过继转移 胰岛素依赖性糖尿病（IDDM）到非肥胖糖尿病（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。 该提案将测试 假设与神经元对应物一样，淋巴细胞 GABA 受体 1）由在不同的亚基上差异表达的亚基组成 发育期间的 T 细胞群，并且 2) 它们的表达可以是 受多种因素调节，包括 T 细胞的激活、配体 GABA-A 受体、细胞因子和胰岛素。 申请人还将测试 淋巴细胞 GABA-A 受体的激活可以调节的假设 T 细胞功能，包括细胞因子和表面分子表达， 和细胞毒性。 申请人将描述其机制 GABA 介导其对 T 细胞的免疫调节作用。 最后，自从GABA 体外抑制 T 细胞增殖和过继转移 体内糖尿病，他们假设 GABA 会抑制抗原特异性 迟发型超敏反应（DTH），以及自发性超敏反应 NOD小鼠体内糖尿病的发展。 证明 GABA 抑制 Th1 介导的体内炎症反应可能会导致新的 抑制T细胞介导的炎症过程的方法和 自身免疫性疾病。 因此，本提案的结果将提供基本的 对 T 细胞神经免疫调节新模式的见解 炎症反应。 此外，该结果可能具有潜在的临床意义 下调人类炎症过程的应用。