LYMPHOCYTIC GABAA RECEPTORS

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 能够调节T细胞反应的生长抑素。γ-氨基丁酸 GABA是中枢神经系统的主要抑制性神经递质 系统。调查人员的初步研究表明，T 细胞表达功能性的GABA-A受体。激活这些GABA-A 受体抑制T细胞增殖和IL-2的产生。此外， 体内应用GABA可抑制小鼠肾小管上皮细胞的过继转移 胰岛素依赖型糖尿病(IDDM)对非肥胖糖尿病(NOD)小鼠的影响。 这些初步发现表明，淋巴细胞GABA受体可以 下调炎症过程。这项提案将考验 假设与神经元受体一样，淋巴细胞GABA受体 1)由亚基组成，这些亚基在不同的 在发育过程中测试细胞群，以及2)它们表达可以是 受多种因素的调节，包括T细胞、配体的激活 用于GABA-A受体、细胞因子和胰岛素。申请者还将测试 淋巴细胞GABA-A受体激活可调节 T细胞功能，包括其细胞因子和表面分子的表达， 和细胞毒性。申请人将描述这种机制(S)的特点 GABA介导其对T细胞的免疫调节作用。最后，由于GABA 体外抑制T细胞增殖及过继转移 糖尿病在体内，他们假设GABA将抑制抗原特异性 迟发性超敏反应(DTH)以及自发的 NOD小鼠体内糖尿病的发生发展。证明了GABA 体内抑制Th1介导的炎症反应可能导致新的 抑制T细胞介导的炎症过程的途径和方法 自身免疫性疾病。因此，这项提案的结果将为 T细胞和T细胞神经免疫调节新模式的研究 炎症反应。此外，这一结果可能具有潜在的临床应用价值。 应用于下调人类的炎症过程。

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.