Mitochondrial Markers of Pollution, Stress, and Neurobehavior

 描述（由申请人提供）：候选人是一名分子流行病学家，主要研究兴趣是产前/早期暴露于环境和社会污染物影响儿童健康的编程机制，特别是神经发育。随着研究将环境空气污染和神经发育不良联系起来，这项提案的目标是通过识别新的线粒体（mt）生物标志物来增加城市空气污染物，压力和神经发育不良之间联系的研究，通过这些生物标志物，子宫内暴露可能会影响未来的神经发育。通过Rosalind Wright，Andrea Baccarelli，Robert Wright，Michelle Bosquet Enlow，Avraham赖兴贝格，Luca Lambertini和Liming Lang博士的正式课程和专家指导，该奖项将使我能够发展成为独立的跨学科环境健康科学家所需的知识和技能，并实现我的长期职业目标：建立一个有竞争力的和成功资助的项目来研究环境暴露的累积效应（例如，空气污染/压力）对儿童慢性病相关生物机制的规划。虽然该奖项侧重于神经行为结果，但值得注意的是，鉴于大量儿童疾病与mt的基础（例如，哮喘、肥胖症、孤独症和注意力障碍）。具体来说，候选人将1）在Baccarelli博士和Lambertini博士的实验室接受广泛的实验室培训，以进一步提高我的分子技能; 2）获得测量和解释涉及社会压力因素的相互作用的培训; 3）在选择，管理和解释整个幼儿期的神经发育评估方面接受指导和实践培训。这项拟议的研究将是第一个研究两种靶组织（例如，胎盘和脐带血）与产前环境暴露（例如，城市空气污染物和压力）和早期神经行为表型。目的是通过一组在母胎界面测量的氧化损伤、异质性和mtDNA丰度的互补标记物（例如，胎盘和脐带血）。这些标记物具有使它们非常适合生物标记物开发的特性，因为它们：1）已被证明会被环境暴露所改变; 2）可以标记受损线粒体的存在，这是大脑特别容易受到的全身氧化应激的主要来源。这项研究亦极具成本效益，因为我们会善用资源， 现有的良好表型的城市和种族混合怀孕队列[PRISM研究]与现有的生物标本和神经行为和环境数据。

 DESCRIPTION (provided by applicant): The candidate is a molecular epidemiologist with primary research interest in the programming mechanisms by which prenatal/early-life exposure to environmental and social pollutants influences the health of children, with particular interest n neurodevelopment. With research linking ambient air pollution and poor neurodevelopment, the goal of this proposal is to add to the growing research linking urban air pollutants, stress and poor neurodevelopment by identifying novel mitochondrial (mt) biomarkers through which in utero exposures may be operating to impact future neurodevelopment. Through formal coursework and expert mentorship by Drs. Rosalind Wright, Andrea Baccarelli, Robert Wright, Michelle Bosquet Enlow, Avraham Reichenberg, Luca Lambertini and Liming Lang, this award will enable me to develop the knowledge and skills necessary to become an independent transdisciplinary environmental health scientist and achieve my long-term career goals: to establish a competitive and successfully funded program to study the cumulative effects of environmental exposures (e.g., air pollution/ stress) on the programming of biological mechanisms related to chronic childhood conditions. While this award focuses on neurobehavioral outcomes, it is worth noting that the knowledge and skills obtained will be broadly applicable to a range of child health outcomes given the large number of childhood conditions with mt underpinnings (e.g., asthma, obesity, autism, and attention disorders). Specifically, the candidate will 1) undergo extensive laboratory training in Drs. Baccarelli's and Lambertini's laboratories to further enhance my molecular skills; 2) obtain training in measuring and interpreting interactions involving social stressors; and 3) receive guidance and hands-on training in selecting, administering and interpreting neurodevelopmental assessments across early childhood. The proposed study will be the first to investigate complementary mtDNA biomarkers in two target tissues (e.g., placenta and cord blood) with respect to prenatal environmental exposures (e.g., urban air pollutants and stress) and early neurobehavioral phenotypes. The intent is to use state-of-art analyses of mtDNA damage by means of a panel of complementary markers of oxidative damage, heteroplasmy, and mtDNA abundance measured at the maternal-fetal interface (e.g., placenta and cord blood). These markers have properties that make them exceptionally well suited to biomarker development, as they: 1) have been shown to be altered by the environmental exposures; and 2) can mark the presence of damaged mitochondria, a primary source of systemic oxidative stress to which the brain is particularly vulnerable. This study is also highly cost effective as we will leverage the resources of an existing well-phenotyped urban and ethnically-mixed pregnancy cohort [PRogramming of Intergenerational Stress Mechanisms (PRISM) study] with existing biospecimens and neurobehavioral & environmental data.