Project 2: Genetic Epidemiology of Neurodevelopmental Metal Toxicity

项目2：神经发育金属毒性的遗传流行病学

• 批准号: 7932376
• 负责人: David C Christiani
• 金额: $ 48.69万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-12 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932376
• 关键词: 2 year old; Address; Age; Arsenic; Arts; Bangladesh; Bioinformatics; Biological; Biological Markers; Birth; Brain; Child; Childhood; Cohort Studies; Communities; Country; Data; Developed Countries; Development; Disease; Environmental Exposure; Environmental Health; Epidemiologist; Exposure to; Gene Silencing; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genotype; In Vitro; Income; Infant Development; Inherited; Investigation; Lead; Lead Poisoning; Life; Manganese; Measures; Metal exposure; Metals; Mexican; Mexico; Mining; Molecular Genetics; Neurodevelopmental Disorder; Oklahoma; Pathway interactions; Phase; Phenotype; Population; Positioning Attribute; Predisposition; Preventive; Process; Prophylactic treatment; Public Health; RNA Interference; Research; Research Personnel; Role; Sampling; Site; Small Interfering RNA; Staging; Superfund; Susceptibility Gene; Tars; Techniques; Technology; Testing; Time; Toxic effect; Toxicogenomics; United States; Validation; Variant; Weight; Work; cohort; cost; density; design; gene environment interaction; genetic epidemiology; genetic variant; genome wide association study; genome-wide; insight; lead exposure; metal poisoning; neurodevelopment; neuronal growth; neuropathology; neurotoxic; neurotoxicity; novel; population based; prenatal; programs; prospective; response; success; superfund site; tool; toxic metal; validation studies; wasting

Metals such as manganese and arsenic are of increasing public health concern since recent data demonstrates their neurotoxicity to the developing brain. However, the role of genetic susceptibility to these toxic metals is unknown. Furthermore, while lead poisoning has been studied extensively, genetic susceptibility to its toxicity is not well understood. A systematic approach to studying gene-environment interaction would have immediate impact on our understanding of how metals induce toxicity and provide biological insight for potential treatment and prevention measures. In this project we will assess data from 3 cohort studies of metals and neurodevelopment. One in a developing country-Bangladesh, where metal exposures are unusually high, one in Mexico, a middle income country where metal exposures are moderately high, and one in a developed Country- (United States) in Tar Creek, OK, where exposure are representative of a community near a US toxic waste site. Tar Creek is a Superfund Megasite and former metal mining community. The success in assembling these cohorts has laid the groundwork for further research in genetic susceptibility to metals. Our 3 cohorts combined yield a sample of 2600 children with prospective data on metal exposure, and repeated neurophenotype measures; sufficient power to discover and to validate genetic susceptibility genes/SNPs. Using a genome-wide approach, we will discover susceptibility variants in a Discovery phase, and then Validate our findings in an independent sample of children while controlling for multiple comparisons. Furthermore, we will integrate with Project 3 (Genetic Mechanisms of Metal Neurotoxicity) to determine other biological pathways relevant to metal toxicity using state of the art siRNA technology to identify genes/pathways which prorriote/inhibit metal toxicity. This project represents perhaps the first large scale coordinated study of genetic susceptibility to metal toxicity and will provide biological insight into the mechanisms by which metals produce toxicity.

自最近数据以来，锰和砷等金属引起了人们的关注 向发育中的大脑展示了它们的神经毒性。但是，遗传易感性的作用 有毒金属尚不清楚。此外，虽然已经对铅中毒进行了广泛的研究，但遗传 对其毒性的敏感性尚不清楚。研究基因环境的系统方法 互动将立即影响我们对金属如何诱导毒性并提供的理解 潜在治疗和预防措施的生物学见解。在这个项目中，我们将评估3个数据 金属和神经发育的队列研究。一个在发展中国家的邦格拉德什，那里的金属 暴露异常高，在墨西哥，一个金属暴露是中等收入的国家 中度高，在一个发达国家（美国）在俄克拉荷马州的塔克里克（美国） 在美国有毒废物遗址附近的社区的代表。塔克里克（Tar Creek）是超级基金会和前一家 金属采矿社区。组装这些队列的成功为进一步的奠定了基础 对金属遗传敏感性的研究。我们的3个队列总共产生了2600名儿童的样本 有关金属暴露的前瞻性数据，并重复进行神经表型测量；足够发现的力量 并验证遗传敏感性基因/SNP。使用全基因组方法，我们会发现 在发现阶段的敏感性变体，然后在独立样本中验证我们的发现 在控制多次比较的同时。此外，我们将与项目3集成（遗传 金属神经毒性的机制）确定与金属毒性相关的其他生物途径 最先进的siRNA技术，以识别预测/抑制金属毒性的基因/途径。这个项目 也许代表了对金属毒性遗传易感性的首次大规模协调研究，将会 提供有关金属产生毒性的机制的生物学洞察力。