Project 4: Determinants of Individual Variablility In As Cytotoxicity

项目 4：As 细胞毒性个体变异的决定因素

• 批准号: 7936597
• 负责人: WALTER T KLIMECKI
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936597
• 关键词: Acids; Area; Arsenic; Biological; Biological Markers; Blood Cells; Candidate Disease Gene; Contracts; Data; Disease; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Exposure to; Gender; Gene Expression; Genes; Genetic Variation; Goals; Health; Health Professional; Human; In Vitro; Individual; Individual Differences; Knowledge; Lymphocyte; Malignant Neoplasms; Measures; Metabolism; Methylation; Microarray Analysis; Nutritional status; Pattern; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Peripheral Nervous System Diseases; Peripheral Vascular Diseases; Policy Maker; Population; Predisposition; Process; Proteins; Public Health; RNA; Reporting; Research; Resistance; Risk Assessment; Risk Factors; Role; Sampling; Series; Source; Testing; Toxic effect; Toxicology; United States; Variant; Weight; base; cytotoxic; cytotoxicity; disorder risk; genome-wide; human disease; lymphoblastoid cell line; resistance factors; response; superfund site; tool; urinary

Arsenic is a global threat to health, and one of the most commonly encountered contaminants in Superfund sites in the United States. Arsenic-exposed populations have been the focus of epidemiological studies that have found a diverse set of human diseases associated with arsenic exposure, including several forms of cancer, peripheral neuropathy, and severe peripheral vascular disease. A natural focus of epidemiological research has been to identify risk factors that predict the fraction of the exposed population that will contract arsenic-associated disease. Validated risk factors include the duration-weighted exposure level of arsenic, gender, nutritional status, genetic variations, and the efficiency of arsenic methylation during its metabolism. Understanding the effect and biological relevance of these risk factors has advanced the field, yet the epidemiological data suggest that there are still significant sources of disease risk that we have not yet identified. This proposal is based on the hypothesis that a key source of disease risk is individual variability in susceptibility to arsenic cytotoxicity, a phenomenon that has been observed in, as one example, limited studies of blood cells from arsenic-exposed humans. In this project we propose to utilize lymphoblastoid cell lines (LBLs) from a total of 130 individuals to characterize the individual variability in susceptibility to arsenic cytotoxicity. Genome-wide gene expression levels will be measured by RNA microarray analysis in order to identify genes whose expression levels correlate with arsenic-resistance level within this in vitro population. Candidate "arsenic resistance" genes will be subject to experimental modulation of gene expression levels in order to validate their functional significance in conferring arsenic resistance. Finally, a set of functionally validated candidate genes that identify the level of arsenic susceptibility will be tested in primary blood cells sampled from individuals at high arsenic exposure compared to a corresponding group of individuals at low arsenic exposure. The long-term goal of this project is twofold: to provide mechanistic information about genes that can reduce arsenic cytotoxicity and to develop additional biomarkers of arsenic-associated disease risk, allowed more refined assessment of risk to real-world populations.

砷是一种全球性的健康威胁，也是美国超级基金场地最常见的污染物之一。砷暴露人群一直是流行病学研究的焦点，这些研究发现了与砷暴露相关的多种人类疾病，包括多种形式的癌症、周围神经病变和严重的周围血管疾病。流行病学研究的一个自然重点是确定风险因素，这些因素可以预测接触人群中感染砷相关疾病的比例。经验证的风险因素包括砷的持续时间加权暴露水平、性别、营养状况、遗传变异和砷代谢过程中甲基化的效率。 了解这些风险因素的影响和生物学相关性推动了该领域的发展，但流行病学数据表明，仍有我们尚未确定的重大疾病风险来源。这一建议是基于这样的假设，即疾病风险的一个关键来源是个体对砷细胞毒性敏感性的差异，这是一种在对砷暴露人体血细胞的有限研究中观察到的现象。在这个项目中，我们建议利用淋巴母细胞系（LBLs）从总共130个人来表征砷细胞毒性的易感性的个体差异。将通过RNA微阵列分析测量全基因组基因表达水平，以鉴定其表达水平与该体外群体中的砷抗性水平相关的基因。候选“抗砷”基因将受到基因表达水平的实验调节，以验证它们在赋予抗砷性中的功能意义。最后，一组功能验证的候选基因，确定砷敏感性的水平将在原代血细胞中进行测试，从高砷暴露的个人相比，在低砷暴露的相应组的个人。该项目的长期目标是双重的：提供有关基因的机制信息，可以减少砷的细胞毒性，并开发砷相关疾病风险的其他生物标志物，允许对现实世界人群的风险进行更精确的评估。