Mechanisms of Immunotoxcity of Chemical Stressors

简介(摘自申请者摘要)：本项目为 继续进行证明使用该地区的可行性的研究 根据皮质酮的浓度-时间曲线(AUC)预测 化学应激源对几种免疫学指标的影响。一个 对压力相关的数量贡献的理解 神经内分泌介体，不仅仅是他们的参与或缺乏参与，是 全面了解化学免疫抑制机制的必要性 压力源。因此，将检验以下假设：数学 使用皮质酮(在小鼠)或皮质醇(在人类)的AUC建模可以 用来说明a)首字母之间的数量关系 糖皮质激素诱导的小鼠分子信号事件，b)影响 急性或28天暴露于应激源对许多免疫学 参数和宿主对癌症或感染的抵抗力，以及C) 小鼠免疫学参数的变化及类似物的变化 人体内的参数。该项目的具体目标是：具体目标1-- 获取数据并建立与皮质酮AUC相关的数学模型 用外源性皮质酮、束缚应激和三种激素治疗的小鼠 化学应激源(丙烷、乙醇和溴氰菊酯) 皮质酮介导的信号转位指标： 糖皮质激素受体与细胞核结合，增加核蛋白结合 与已知与糖皮质激素受体和核因子-KB结合的DNA序列，增加 1kb蛋白在细胞质中的浓度，并降低了 核转录因子-kB在细胞核内。具体目标2--获取数据和发展数学 用小鼠急性和28天暴露于外源性皮质酮的模型， 束缚应激，以及与皮质酮AUC相关的三种化学应激源 BI6F1 0肿瘤的免疫学参数选择及宿主抵抗力研究 细胞和旋毛虫。具体目标3--获取数据和开发 皮质醇AUC与选定免疫学参数的数学模型 在接受外源性皮质醇治疗的受试者中， 一段时间。具体目标4--使用在具体目标中开发的模型 1-310确定所检查的参数之间的定量关系 并开发预测模型，以允许估计 化学应激源对人体免疫学参数和宿主抵抗力的影响。 如果假设是正确的，这里得到的结果将改善风险。 通过合理估计化学应激源的影响进行评估 关于人类免疫功能和对感染和癌症的抵抗力 基于小鼠的实验结果。

DESCRIPTION (Adopted from the Applicant's Abstract): This project is a continuation of studies that demonstrated the feasibility of using the area under the concentration vs. time curve (AUC) for corticosterone to predict the effects of chemical stressors on several immunological parameters. An understanding of the quantitative contributions of stress-related neuroendocrine mediators, not just their involvement or lack of involvement, is necessary to fully understand the mechanisms of immunosuppression by chemical stressors. Therefore, the following hypothesis will be tested: Mathematical modeling using the AUC for corticosterone (in mice) or cortisol (in humans) can be used to demonstrate quantitative relationships between a) the initial molecular signaling events induced by glucocorticoids in mice, b) the effects of acute or 28-day exposure to stressors on a number of immunological parameters and on host resistance to cancer or infection in mice, and C) alteration of immunological parameters in mice and alteration of analogous parameters in humans. The Specific Aims for the project are: Specific Aim 1 - Acquire data and develop mathematical models relating corticosterone AUC in mice treated with exogenous corticosterone, restraint stress, and three chemical stressors (propanil, ethanol, and deltamethrin) to the following indicators of corticosterone-mediated signaling: translocation of glucocorticoid receptor to the nucleus, increased binding of nuclear proteins to DNA sequences known to bind glucocorticoid receptor and NF-KB, increased concentration of 1KB protein in the cytoplasm, and decreased concentration of NF-kB in the nucleus. Specific Aim 2- Acquire data and develop mathematical models using acute and 28- day exposure of mice to exogenous corticosterone, restraint stress, and three chemical stressors to relate corticosterone AUC to selected immunological parameters and to host resistance against Bi 6F1 0 tumor cells and Trichinella spiralis. Specific Aim 3- Acquire data and develop mathematical models relating cortisol AUC and selected immunological parameters in human subjects treated with an infusion of exogenous cortisol for various periods of time. Specific Aim 4 - Use the models developed in Specific Aims 1-310 determine the quantitative relationships between the parameters examined and to develop predictive models that will allow estimation of the effects of chemical stressors on immunological parameters and host resistance in humans. If the hypothesis is correct, the results obtained here will improve risk assessment by allowing rational estimates of the effects of chemical stressors on immune function and resistance to infection and cancer in humans on the basis of results from mice.