CALCIUM AND POTASSIUM CHANNELS IN LYMPHOCYTE

淋巴细胞中的离子通道具有多种功能， 包括抗原诱导的细胞内钙离子升高 与T细胞受体结合，并分泌淋巴因子和 扩散。这些功能中的许多又是由 内源性和外源性物质，如儿茶酚胺， 类固醇、神经递质、尼古丁和滥用药物 就像疾病状态一样。最近的许多证据已经积累到 提出了免疫调节物质或疾病的假设 可能通过改变细胞内的 淋巴细胞膜通道的特性。这是我们的主要目标 这一建议旨在通过以下方式阐明细胞和分子机制 哪些淋巴细胞通道可以激发、决定和调节免疫 回应。利用荧光和膜片钳记录技术，我们 我将研究三种淋巴细胞离子的性质和调节 人类淋巴母细胞系中的通道，n型电压 依赖性钾通道K(V)，钙依赖性钾 K(Ca)通道与钙释放激活的钙通道 (Crac)。这些频道的特性将在 某些类固醇激素，黄体酮和雌二醇的影响，以及 新的海洋西膜类化合物，它们是来源于 加勒比软珊瑚(柳珊瑚)。类固醇和毒素会 检查它们对细胞内钙动员和细胞内钙的影响 K(V)和K(Ca)的活化和失活动力学 通道，以及对ICRAC(流经CRAC通道的电流)的影响。 关于T淋巴细胞通道特性及其相关信息的研究进展 规则将对设计新的治疗方法非常有用 药剂，主要针对这些膜离子通道。这项工作 这里提出的建议将增加我们关于T细胞调节的信息 通道及其免疫调节功能，并将有助于进一步 我们对免疫反应的理解以及如何管理它 在免疫缺陷、自身免疫状态下， 炎症和其他疾病。

Ion channels in lymphocytes subserve a variety of functions, including the rise in intracellular calcium induced by antigen binding to the T cell receptor, and lymphokine secretion and proliferation. Manyof these functions are in turn modulated by endogenous and exogenous substances, such as catecholamines, steroids, neurotransmitters, and nicotine and drugs of abuse, as well as by disease states. Much recent evidence has accumulated to suggested the hypothesis that immunomodulating substances or diseases may induce or inhibit particular immune functions by altering the properties of lymphocyte membrance channels. It is the major goal of this proposal to elucidate the cellular and molecular mechanisms by which lymphocyte channels initate, determine and regulate the immune response. Using fluorescence and patch clamp recording techniques we will study the properties and regulation of three lymphocyte ion channels in a human lymphoblastoid cell line, the n type voltage dependent potassium channel K (V), the calcium dependent potassium channel K (Ca) and the calcium release-activated calcium channel (CRAC). The properties of these channels will be studied under the effects of certain steroid hormones, progesterone and estradiol, and novel marine cembranoids, which are diterpenoid toxins derived from Caribbean soft corals (gorgonians). The steroids and toxins will be examined for their effects on intracellular calcium mobilization and activation and inactivationkinetics in both the K (V) and K (Ca) channels, and for effects on Icrac (current through CRAC channels). The information obtained on T lymphocyte channel properties and their regulationwillb e very useful for the design of novel therapeutic agents, mainly targeted at these membrane ionic channels. The work proposed here will add to our information on the regulation of T cell channels and their immunomodulatory function, and will help further our understanding of the immune response and how to manage it successfully in states of immunodeficiency, autoimmunity, inflammation, and other disorders.