CD4+ T cell-mediated neurotoxicity with continuous trichloroethylene exposure

描述（由申请人提供） 三氯乙烯（TCE）是一种工业溶剂和超级基金化学品，由于处置不当，在美国各地的地下水和饮用水供应中可以检测到低水平的三氯乙烯。几项流行病学研究记录了在子宫内或在生命早期通过母体接触三氯乙烯的儿童的神经和行为障碍。使用研究人员的小鼠模型，他们实验室的研究表明，低水平的早期生活或仅妊娠暴露会促进氧化应激，与类似于注意力缺陷多动障碍儿童的异常行为有关。研究人员不知道TCE暴露如何介导神经毒性和不良行为。K 02独立科学家发展奖申请将使候选人能够开发一个研究计划，其目标是测试以下假设：在整个妊娠期和生命早期持续暴露于比以前使用的更低水平的TCE会改变大脑中的神经保护因子，导致氧化应激和不良行为，而不是仅在妊娠期或生命早期暴露（目标1）。因为他们已经表明CD 4 + T细胞是TCE发育毒性的早期靶点，研究人员将测试新的假设，即失调的CD 4 + T细胞有助于在我们的模型中观察到的不良神经学结果（目的2）。 将使用TCE处理的MRL+/+小鼠的CD 4 + T细胞进行连续转移实验，检测其过继转移至实验室中产生的淋巴细胞缺陷型（Rag敲除）MRL+/+小鼠后促进不良神经行为的能力。该K 02将有助于培养候选人实现这些研究目标的能力，为她提供受保护的时间，使她更充分地参与NIH资助的R 01资助项目，该项目旨在研究发育暴露于TCE是否加速MRL+/+小鼠自身免疫的发展。这也将使她能够专注于她的职业目标，以检查CD 4 + T细胞和神经系统结果之间的相互作用。 候选人的职业发展计划涉及神经行为技术和实验模型和儿童分析的强化培训，将增强她在这一领域的知识和技能。K 02将具有关键价值，以扩大候选人的研究计划，并有可能发现 TCE神经毒性的作用机制未知，可能为TCE暴露儿童的营养或抗氧化支持疗法铺平道路。

DESCRIPTION (provided by applicant) Trichloroethylene (TCE) is an industrial solvent and Superfund chemical that can be detected at low levels in groundwater and drinking water supplies across the U.S. due to inappropriate disposal. Several epidemiological studies have documented neurologic and behavioral disorders in children exposed to TCE in utero or in early life through maternal exposure. Using the investigators' mouse model, studies in their laboratory have shown that low level early life- only or gestational-only exposure promotes oxidative stress in association with abnormal behavior similar to children with attention-deficit hyperactivity disorder. The investigators do no know how TCE exposure mediates neurotoxicity and adverse behavior. This K02 independent Scientist Development Award application will enable the candidate to develop a program of research whose goal is to test the hypothesis that continuous developmental exposure occurring throughout gestation and early life to even lower levels of TCE than used previously alters neuroprotective factors in the brain leading to oxidative stress and adverse behavior over that of gestational-or early life-exposure only (aim 1). Because they have shown that CD4+ T cells are early-life targets of TCE developmental toxicity, the investigators will test the novel hypothesis that dysregulated CD4+ T cells contribute to adverse neurologic outcome observed in our model (aim 2). Adoptive transfer experiments using CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to promote adverse neurobehavior following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice generated in their laboratory. This K02 will help foster the candidate's ability to achieve these research goals by providing her with protected time to be more fully engaged in her NIH-funded R01 funded project designed to examine whether developmental exposure to TCE accelerates the development of autoimmunity in MRL+/+ mice. It will also allow her to focus on her career goals to examine the interaction between CD4+ T cells and neurological outcome. The candidate's Career Development Plan involving intense training in neurobehavioral techniques and analysis in both experimental models and in children will enhance her knowledge and skills in this area. The K02 will be of critical value to expand the candidate's research program with the potential to discover unknown mechanisms of action of TCE neurotoxicity that may pave the way to nutritional or anti- oxidant support therapies in TCE-exposed children.