Immune dysfunction associated with early life heavy metal exposure

与生命早期重金属暴露相关的免疫功能障碍

• 批准号: 8435492
• 负责人: Emily Catherine Somers
• 金额: $ 13.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435492
• 关键词: Accounting; Active Learning; Address; Adolescence; Age; Allergic; Allergic Disease; Antibodies; Antinuclear Antibodies; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Markers; Birth; Breast Feeding; Cause of Death; Cell Differentiation process; Child; Childhood; Chronic; Chronic Disease; Cohort Studies; Cytokine Gene; DNA Methylation; Data Set; Descriptive Epidemiology; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Environmental Epidemiology; Environmental Health; Epidemiologist; Epigenetic Process; Equilibrium; Etiology; Exposure to; Fetal Development; Frequencies; Genes; Genetic Variation; Goals; Growth; Health; Health Policy; Heavy Metals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunologist; Immunology; Immunotoxicology; Knowledge; Laboratory Research; Lead; Learning; Life; Link; Locus Control Region; Longevity; Lupus; Measurement; Measures; Mediating; Mentorship; Mercury; Metal exposure; Methods; Methylation; Mexico; Modeling; Molecular Epidemiology; Pharmacoepidemiology; Phenotype; Population; Population Study; Population Surveillance; Predisposition; Principal Investigator; Public Health; Qualifying; Quality of life; Registries; Regulatory T-Lymphocyte; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; Staging; Stimulus; Structure; T-Lymphocyte; Time; Toxic Environmental Substances; Training; Woman; career; career development; clinical epidemiology; cohort; cytokine; demethylation; design; early childhood; early life exposure; epidemiology study; experience; fetal; gene environment interaction; human disease; in utero; microbial; middle age; population based; prenatal; programs; rheumatologist; sex

DESCRIPTION (provided by applicant) The overarching goal of this K01 proposal is for the candidate to acquire the expertise necessary to lead a research program in environmental epidemiology applied to immune-mediated disorders. Dr. Somers is trained as an epidemiologist, with significant expertise in the clinical epidemiology of lupus, public health surveillance of chronic disease, and descriptive epidemiology of autoimmune diseases. Immediate career goals are to expand on this background by acquiring comprehensive training in relevant areas in environmental health sciences, including molecular epidemiology, immunotoxicology, and epigenetics. Long-term career goals are to unravel the etiologies of autoimmune and other immune-mediated disorders, an in particular, to identify the role of potentially modifiable early life exposures. The proposed training and research will be conducted under the mentorship of Howard Hu, M.D. MPH Sc.D. and Bruce Richardson, M.D. Ph.D. Dr. Hu is a recognized leader in environmental epidemiology and health effects of heavy metals. Dr. Richardson is a rheumatologist and immunologist, and has performed groundbreaking laboratory research related to epigenetics and lupus. The Career Development Plan will include both structured and informal learning activities that together will provide in depth training in the following growth areas for the candidate: (a) Environmental health science and molecular epidemiology, including exposure assessment, gene-environment interactions, and immunotoxicology; (b) developmental and maternal-fetal immunology; (c) assessment and interpretation of biomarkers of immune phenotype and function; (d) epigenetics methods, including DNA methylation, related to health and human disease. The proposed research will be a birth cohort study investigating the association between early life heavy metal exposure and immune dysregulation. The study population will be the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort (PI: Dr. Hu), which has been extensively characterized in terms of heavy metal exposures, including mercury (prenatal and childhood measurement). This proposal will be the first to investigate immunologic endpoints in this birth cohort. Emphasis will be exploration of the association between in utero and early childhood exposure to mercury and immune perturbations, which may be relevant in terms of autoimmune and allergic disease. Immune parameters will include auto-antibodies, cytokines, and gene-specific methylation levels relevant to T helper cell differentiation. Balance of Th subsets is important in directing host immune responses, and clearly influenced by microbial stimuli. This project addresses a critical gap in knowledge in the role of non-microbial exposures in immune modeling, and will represent a significant career enhancement opportunity for the candidate.

描述（由申请人提供） K01 提案的总体目标是让候选人获得领导针对免疫介导疾病的环境流行病学研究项目所需的专业知识。 Somers 博士接受过流行病学家培训，在狼疮临床流行病学、慢性病公共卫生监测和自身免疫性疾病描述流行病学方面拥有丰富的专业知识。 近期的职业目标是通过获得环境健康科学相关领域的全面培训来扩展这一背景，包括分子流行病学、免疫毒理学和表观遗传学。 长期职业目标是揭示自身免疫性疾病和其他免疫介导疾病的病因，特别是确定早期生命暴露的潜在可改变的作用。 拟议的培训和研究将在医学博士、公共卫生硕士霍华德·胡 (Howard Hu) 的指导下进行。和布鲁斯·理查森（Bruce Richardson）医学博士 胡博士是环境流行病学和重金属健康影响方面公认的领导者。理查森博士是一位风湿病学家和免疫学家，并进行了与表观遗传学和狼疮相关的开创性实验室研究。职业发展计划将包括结构化和非正式的学习活动，这些活动将为候选人提供以下成长领域的深入培训： (a) 环境健康科学和分子流行病学，包括暴露评估、基因-环境相互作用和免疫毒理学； (b) 发育和母胎免疫学； (c) 免疫表型和功能生物标志物的评估和解释； (d) 表观遗传学方法，包括与健康和人类疾病相关的 DNA 甲基化。 拟议的研究将是一项出生队列研究，调查生命早期重金属暴露与免疫失调之间的关联。研究人群将是墨西哥生命早期暴露于环境有毒物质 (ELEMENT) 出生队列（PI：胡博士），该队列已在重金属暴露方面进行了广泛的表征，包括汞（产前和儿童测量）。该提案将是第一个研究该出生队列中免疫学终点的提案。 重点是探索子宫内和幼儿期接触汞与免疫扰动之间的关系，这可能与自身免疫和过敏性疾病有关。 免疫参数包括自身抗体、细胞因子和与 T 辅助细胞分化相关的基因特异性甲基化水平。 Th 亚群的平衡对于指导宿主免疫反应很重要，并且明显受到微生物刺激的影响。该项目解决了非微生物暴露在免疫建模中的作用方面的一个关键知识空白，并将为候选人提供一个重要的职业提升机会。