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：
8755026
负责人：
SARAH J BLOSSOM
金额：
$ 11.89万
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/8755026
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 Folate 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 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物质，由于不适当的处理，在美国的地下水和饮用水供应中可以在低水平中检测到。几项流行病学研究已记录了子宫内与TCE的儿童的神经系统和行为障碍，或者通过孕产妇暴露在早期生活。使用研究者的小鼠模型，其实验室的研究表明，低水平的早期寿命或仅妊娠暴露会促进氧化应激，而异常行为与患有注意力缺陷多动障碍的儿童相似。研究人员不知道TCE暴露如何介导神经毒性和不良行为。这项K02独立科学家发展奖的应用程序将使候选人能够制定一项研究计划，该计划的目标是检验一个假设，即在妊娠期间和早期生活中发生持续的发育暴露，甚至比以前使用过的更低的TCE水平更低，从而改变了大脑中的神经保护因素，从而导致氧化应激，导致氧化应激和不利的行为，而早期生命的生命曝光只有早期的生活曝光（AIL-AIL 1）。因为他们表明CD4+ T细胞是TCE发育毒性的早期寿命靶标，因此研究者将检验一个新的假设，即失调的CD4+ T细胞在我们的模型中观察到不良神经系统结果（AIM 2）。使用来自TCE处理的MRL+/+小鼠的CD4+ T细胞的收养转移实验，将测试其在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K02将通过为她提供受保护的时间以更充分地参与其NIH资助的R01资助的项目来帮助促进候选人实现这些研究目标的能力，旨在检查TCE的发展暴露是否会加速MRL+/+小鼠自身免疫性的发展。这也将使她专注于自己的职业目标，以研究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在实验模型和儿童中进行神经行为技术和分析的激烈培训，将增强她在这一领域的知识和技能。 K02将具有至关重要的价值，以扩大候选人的研究计划，并有可能发现 TCE神经毒性作用的未知机制可能为TCE暴露儿童的营养或抗氧化剂支持疗法铺平道路。