CD4+ T cell-mediated neurotoxicity with continuous trichloroethylene exposure

持续接触三氯乙烯导致 CD4 T 细胞介导的神经毒性

基本信息

批准号：
8926236
负责人：
SARAH J BLOSSOM
金额：
$ 13.47万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926236
关键词：
Adenosine Adoptive Transfer Adult Age Antioxidants Appearance Area Attention deficit hyperactivity disorder Autoimmune Diseases Autoimmune Process Autoimmunity Award Behavior Behavior Disorders Betaine Biological Markers Birth Brain Brain region CD4 Positive T Lymphocytes Child Childhood Choline Cystathionine Cysteine Cystine DNA Development Development Plans Dietary Intervention Disease Environmental Exposure Environmental Pollutants Environmental Risk Factor Epidemiologic Studies Experimental Models Exposure to Female Figs - dietary Flowers Folic Acid Fostering Funding Glutathione Glutathione Disulfide Goals Grant Homocysteine Homocystine Immune System Diseases Immune system Independent Scientist Award Inflammation Interferon Type II Knock-out Knowledge Laboratories Lead Life Lymphocyte Maternal Exposure Mediating Metabolic Pathway Metabolism Methionine Methylation Modeling Mus National Institute of Environmental Health Sciences Nature Neurodevelopmental Disorder Neurological outcome Nutritional Organic solvent product Oxidative Stress Oxidative Stress Pathway Peripheral Predisposition Pregnancy Productivity Research Research Personnel Role Scientist Solvents Staging Subarachnoid Hemorrhage System Techniques Testing Therapeutic Time Toxic effect Training Trichloroethylene United States National Institutes of Health Vitamin B 12 Water Water Pollutants Water Supply Work Zinc autism spectrum disorder career career development cysteinylglycine design developmental neurotoxicity developmental toxicity drinking water early life exposure exposed human population functional outcomes in utero insight male mouse model nervous system disorder neurobehavior neurobehavioral neuroprotection neurotoxic neurotoxicity novel offspring oxidative damage pollutant postnatal prevent programs public health relevance remediation research study skills superfund chemical toxicant

项目摘要

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.

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含量的三氯乙烯。一些流行病学研究记录了在子宫内或在生命早期通过母亲接触TCE的儿童出现神经和行为障碍的情况。使用研究人员的小鼠模型，他们实验室的研究表明，低水平的生命早期或妊娠期暴露会促进氧化应激，并与类似于患有注意力缺陷多动障碍的儿童的异常行为相关。研究人员不知道三氯乙烯暴露如何介导神经毒性和不良行为。这项 K02 独立科学家发展奖申请将使候选人能够开发一项研究计划，其目标是检验以下假设：在整个妊娠期和生命早期，持续发育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，从而导致与仅妊娠期或早期生命暴露相比，对氧化应激和不良行为的影响（目标 1）。因为他们已经证明 CD4+ T 细胞是 TCE 发育毒性的早期目标，所以研究人员将测试新的假设，即失调的 CD4+ T 细胞会导致我们模型中观察到的不良神经系统结果（目标 2）。使用 TCE 处理的 MRL+/+ 小鼠的 CD4+ T 细胞进行过继转移实验，将测试其在过继转移至实验室生成的淋巴细胞缺陷（Rag 敲除）MRL+/+ 小鼠后促进不良神经行为的能力。 K02 将为候选人提供受保护的时间，让她更充分地参与 NIH 资助的 R01 资助项目，该项目旨在检查 TCE 的发育暴露是否会加速 MRL+/+ 小鼠自身免疫的发展，从而帮助培养候选人实现这些研究目标的能力。它还将使她能够专注于自己的职业目标，以检查 CD4+ T 细胞与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以及实验模型和儿童分析的强化培训，这将增强她在该领域的知识和技能。 K02 对于扩展候选人的研究计划具有至关重要的价值，有可能发现 TCE 神经毒性的未知作用机制可能为接触 TCE 的儿童的营养或抗氧化支持治疗铺平道路。