ION CHANNELS IN LYMPHOCYTES: GENETIC PROBES

钾(K)通道控制着广泛的生理过程， 包括膜电位和细胞体积的调节 组织，以及神经系统中电兴奋性的调节。 我们的研究揭示了T细胞中三种不同类型的钾通道 淋巴细胞(n，n‘和L)在有丝分裂原激活和释放中起作用 差异化。这些通道的表达取决于 对T细胞的表型和活化分化状态的影响。 我们还发现了T细胞K通道表达改变之间的联系 淋巴细胞与四种不同的自身免疫性疾病：系统性红斑狼疮 红斑狼疮、1型糖尿病、类风湿性关节炎和 多发性硬化症。使用分子技术，我们已经表征了 人T细胞中编码n型和L K通道的基因 已确定了14个相关K通道基因的染色体位置。 针对T细胞K通道蛋白的抗肽抗体有 使我们能够开始测量通道蛋白的周转率 T细胞。在这项建议中，我们计划将我们的研究扩展到进一步 明确K通道在T细胞活化和分化中的作用。 拟议实验的总体目标有三个方面。首先，我们 将映射编码T细胞K通道的转录本，并识别 组织特异的和依赖于激活的调节元件。第二，我们 将测量T细胞K的合成和降解率 在T和B细胞激活和发育过程中的通道转录。 第三，我们将利用抗肽抗体研究通道蛋白 淋巴细胞的周转。正常和疾病T细胞的比较 可能揭示与通道相关的基因或蛋白质调节异常 具有自身免疫力。在这些研究过程中，我们可能会揭示DNA 调节T细胞K通道基因活性的结合蛋白 扩散。

Potassium (K) channels control a wide array of physiological processes, including regulation of membrane potential and cell volume in diverse tissues, and modulation of electrical excitability in the nervous system. Our studies have revealed three distinct types of K channels in T lymphocytes (n, n' and l) that play a role in mitogen-activation and differentiation. Expression of these channels is dependent on the phenotype and on the activation and differentiation status of T cells. We have also identified a link between altered K channel expression in T lymphocytes and four disparate autoimmune disorders: systemic lupus erythematosus, type-1 diabetes mellitus, rheumatoid arthritis and multiple sclerosis. Using molecular techniques we have characterized the genes encoding the types n and l K channels in T cells; the human chromosomal locations of 14 related K channel genes have been determined. Anti-peptide antibodies against the T cell K channel proteins have allowed us to start measuring the rate of turnover of channel proteins in T cells. In this proposal we plan to extend our studies to further define the role of K channels in T cell activation and differentiation. The overall goal of the proposed experiments is three-fold. First, we will map the transcripts encoding T cell K channels, and identify tissue-specific and activation-dependent regulatory elements. Second, we will measure the rate of synthesis and degradation of the T cell K channel transcripts during T and B cell activation and development. Third, using anti-peptide antibodies we will study channel protein turnover in lymphoid cells. Comparison of normal and diseased T cells may reveal abnormalities In channel-gene or protein regulation associated with autoimmunity. In the course of these studies we may reveal DNA binding proteins that modulate K channel-gene activity during T cell proliferation.