Disruption of Lymphocyte Signal Transduction by HG+2

描述(申请人提供)：水星是一种广泛的环境 对神经系统和免疫系统有潜在毒性的污染物 为人所知。令人惊讶的是，人们对其分子作用机制知之甚少。 虽然高水平接触不再常见，但大部分人口 由于无处不在的汞，目前吸收低水平(-.10微克/天)的汞 环境因素，包括空气、食物、水和牙科汞齐。为 约3%的人口没有已知的特殊危险因素，血液 汞含量超过0.25微米。4%的人口超过0.125微米 尿中的汞，报告的浓度最高的是患有 目前尚无已知的特殊危险因素为1um左右。初步的和最近的 我们实验室公布的结果支持我们的假设 0.1-1.0um范围内的无机汞浓度可直接 破坏免疫系统动态平衡，并通过以下方式导致自身免疫性疾病 干扰蛋白酪氨酸磷酸化(PTK)介导的信号 转导，意味着相当数量的个体可能在不知不觉中 处于危险之中。在这项提案中，我们的目标是批判性地 在几个不同的细胞系统中全面测试我们的假设 自身免疫性疾病。特别是，我们将测试水星的能力 干扰抗原受体介导和P1K依赖的信号转导 以及在已建立的T和B细胞系中的增殖控制 新鲜分离的人外周血淋巴细胞。我们还将研究 低浓度汞对抗原受体介导的影响 淋巴细胞中的细胞凋亡。

DESCRIPTION (provided by applicant): Mercury is a widespread environmental contaminant whose toxic potential to the nervous and immune systems is well known. Surprisingly little is known about its molecular mechanism of action. While high level exposure is no longer common, large segments of the population currently absorb low (-.10 ug/day) levels of mercury as a result of ubiquitous environmental factors, including air, food, water, and dental amalgam. For about 3 percent of the population with no known special risk factors, blood levels of mercury exceed 0.25 uM. 4 percent of the population exceed 0.125 uM mercury in urine, with the highest concentrations reported in individuals with no known special risk factors to be about 1 uM. Preliminary and recently published results from our laboratories support our hypothesis that concentrations of inorganic mercury in the range of 0.1- 1.0 uM may directly impair immune system homeostasis, and contribute to autoimmune disease by interfering with protein tyrosine phosphorylation (PTK)mediated signal transduction, implying that substantial numbers of individuals may unknowingly be at risk. In this proposal it is our objective to critically and comprehensively test our hypothesis in several different cell systems relevant to autoimmune disease. In particular, we will test mercury's ability to interfere with antigen receptor mediated and P1K-dependent signal transduction and proliferative control in established T and B cell lines, as well as in freshly isolated human peripheral blood lymphocytes. We will also examine the effect that low concentrations of mercury have on antigen receptor mediated apoptosis in lymphocytes.