Mitochondrial Markers of Pollution, Stress, and Neurobehavior

污染、压力和神经行为的线粒体标记

• 批准号: 9446067
• 负责人: Kelly J Brunst
• 金额: $ 24.83万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9446067
• 关键词: Accounting; Address; Adenosine; Affect; Age-Months; Air Pollutants; Air Pollution; Animals; Asthma; Attention; Autistic Disorder; Award; Biochemical; Biological; Biological Markers; Blood; Brain; Breathing; Caliber; Carbon Black; Cell physiology; Child; Child health care; Childhood; Chronic; Cognition; DNA Damage; DNA copy number; Data; Disease; Encephalitis; Environmental Exposure; Environmental Health; Epidemiologist; Equilibrium; Event; Exhibits; Exposure to; Funding; Future; Goals; Histologic; Human; Infant; Infant Behavior; Inflammation; Knowledge; Laboratories; Leukocytes; Life; Limes; Link; Literature; Maternal-Fetal Exchange; Measures; Mediating; Mediation; Memory; Mentorship; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mothers; Mutation; Neuraxis; Obesity; Outcome; Oxidative Stress; Oxidative Stress Induction; Particulate Matter; Pathology; Pathway interactions; Phenotype; Placenta; Play; Pollution; Pregnancy; Prevention strategy; Property; Psychological Stress; Rattus; Reactive Oxygen Species; Research; Resources; Respiratory System; Respiratory tract structure; Risk; Role; Scientist; Seasons; Site; Social Interaction; Source; Stream; Stress; Testing; Tissues; Toxic effect; Training; Trauma; Umbilical Cord Blood; Umbilical cord structure; ambient air pollution; behavioral impairment; behavioral outcome; biomarker development; career; cohort; cost effective; design; early childhood; early life exposure; epidemiology study; executive function; experience; fetal; frontal lobe; improved; in utero; interest; intergenerational; laboratory experience; maternal stress; mitochondrial dysfunction; neurobehavior; neurobehavioral; neurodevelopment; novel; novel marker; oxidation; oxidative damage; particle; pollutant; prenatal; prenatal environmental exposure; prenatal exposure; programs; public health relevance; repetitive behavior; skills; social; social engagement; social stress; stressor; traffic-related air pollution; tripolyphosphate; ultrafine particle

 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.

 描述（由申请人提供）：候选人是一位分子流行病学家，主要研究编程机制，通过该机制，产前/生命早期接触环境和社会污染物会影响儿童的健康，特别关注神经发育。通过将环境空气污染与神经发育不良联系起来的研究，该提案的目标是通过识别新的线粒体（mt）生物标志物来补充日益增多的将城市空气污染物、压力和神经发育不良联系起来的研究，通过这些生物标志物，子宫内的暴露可能会影响未来的神经发育。通过博士的正式课程和专家指导。 Rosalind Wright、Andrea Baccarelli、Robert Wright、Michelle Bosquet Enlow、Avraham Reichenberg、Luca Lambertini 和 Liming Lang，该奖项将使我能够发展成为一名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：建立一个有竞争力且成功资助的项目来研究环境暴露（例如空气）的累积影响 污染/压力）对与慢性儿童疾病相关的生物机制的规划。虽然该奖项侧重于神经行为结果，但值得注意的是，鉴于大量儿童疾病具有 mt 基础（例如哮喘、肥胖、自闭症和注意力障碍），所获得的知识和技能将广泛适用于一系列儿童健康结果。具体来说，候选人将 1) 接受广泛的博士实验室培训。 Baccarelli 和 Lambertini 的实验室进一步提高了我的分子技能； 2) 获得测量和解释涉及社会压力源的互动的培训； 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。拟议的研究将是第一个调查两个目标组织（例如胎盘和脐带血）中与产前环境暴露（例如城市空气污染物和压力）和早期神经行为表型相关的互补线粒体DNA生物标志物的研究。目的是通过一组氧化损伤、异质性和在母胎界面（例如胎盘和脐带血）测量的 mtDNA 丰度的互补标记，对 mtDNA 损伤进行最先进的分析。这些标记物具有使其非常适合生物标记物开发的特性，因为它们：1）已被证明会因环境暴露而改变； 2）可以标记受损线粒体的存在，线粒体是全身氧化应激的主要来源，大脑特别容易受到这种应激的影响。这项研究也具有很高的成本效益，因为我们将利用资源 现有的表型良好的城市和种族混合妊娠队列[代际压力机制（PRISM）研究的编程]与现有的生物样本以及神经行为和环境数据。