Application of Functional Genomics for Identifying Modifiers of Susceptibility

功能基因组学在识别易感性修饰因素中的应用

• 批准号: 7651335
• 负责人: Russell S Thomas
• 金额: $ 21万
• 依托单位: THE HAMNER INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651335
• 关键词: Address; Adverse effects; Affect; Age; Biological Markers; Bronchitis; Cell Line; Cells; Chronic Disease; Collagen; Communities; Complement; Complementary DNA; DNA; DUSP1 gene; Data; Development; Diabetes Mellitus; Diet; Disease Pathway; Dose; Environmental Hazards; Environmental Health; Epidemiologic Studies; Epithelial; Epithelial Cells; Fibroblasts; Figs - dietary; Future; G-Protein-Coupled Receptors; Gender; Gene Expression; Gene-Modified; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Human; IL8 gene; Individual; Inflammation; Inflammatory; Inflammatory Response; Length; Libraries; Life Style; Measures; Methods; Modeling; Monitor; Nutritional; Occupational; Occupational Diseases; Occupational Exposure; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Play; Population; Predisposition; Pregnancy; Process; Production; Publishing; RNA Interference; Research; Research Personnel; Research Project Grants; Resources; Respiratory System; Respiratory tract structure; Robotics; Role; Single Nucleotide Polymorphism; Source; System; Technology; Testing; Toxic effect; Transfection; United States; Vanadium; airway inflammation; base; connective tissue growth factor; functional genomics; gain of function; inflammatory marker; innovation; knock-down; lifestyle factors; loss of function; novel strategies; respiratory; response; success; tool; toxicant; vanadium pentoxide

DESCRIPTION (provided by applicant): Protecting individuals from the adverse effects of occupational exposures requires addressing the variability in human response and identifying workers with increased susceptibility. Genetics, environmental, and lifestyle factors all contribute to the variability in the human response. The primary objective of this project is to develop an innovative approach to identify potential modifiers of susceptibility to occupational exposures. We hypothesize that variability in gene expression due to age, gender, nutritional state, chronic diseases, and lifestyle factors underlie some of the differences in worker susceptibility to adverse respiratory tract effects from occupational exposures. Large-scale gain-of-function and loss-of-function genomic screens can be used to model the inherent diversity in gene expression within a population and identify those genes whose increase or decrease in expression may modify the susceptibility to adverse effects from occupational exposures. To evaluate this hypothesis, we will use vanadium pentoxide (V2O5) treatment of human bronchial epithelial cells as a model for occupational bronchitis and IL-8 production as a surrogate for inflammation. In the first specific aim of this proposal, we will identify positive modifiers of susceptibility to vanadium-induced airway inflammation using large scale gain-of-function and loss-of-function genomic screens. The genomic screens will identify which genes, with altered expression, increase IL-8 production in the presence of a sub-inflammatory V2O5 exposure. In the second specific aim, we will identify negative modifiers of susceptibility to vanadium-induced airway inflammation using large scale gain-of-function and loss-of-function genetic screens. The genomic screens will identify which genes, with altered expression, decrease IL-8 production in the presence of an inflammatory V2O5 exposure. In the final specific aim, we will confirm the results of the primary screens and evaluate the activity of the positive and negative modifiers using other vanadium-responsive biomarkers. Through these specific aims, we will assemble a complete picture of the gene expression changes that affect vanadium-induced bronchitis and provide a means to address potential nutritional and lifestyle factors that may make workers more or less susceptible to the respiratory effects. On a larger scale, the development of this approach will be significant for the environmental health community as a whole by providing a generalizable method that can identify gene expression changes underlying susceptibility to numerous occupational and environmental hazards. PROJECT NARRATIVE: Protecting individuals from the adverse effects of occupational exposures requires understanding variability within the population and identifying workers with increased susceptibility. An individual's DNA, diet, chronic diseases (e.g., diabetes), and lifestyle factors all contribute to the variability between individual workers. In this research project, we will develop an approach to mimic differences in the amount of a gene that an individual worker expresses and whether those differences make the worker more or less susceptible to the adverse effects from occupational exposures.

描述（由申请人提供）：保护个人免受职业暴露的不利影响，需要解决人类反应的可变性，并确定易感性增加的工人。遗传学，环境和生活方式因素都导致人类反应的变异性。该项目的主要目的是开发一种创新的方法，以确定对职业暴露易感性的潜在修饰符。我们假设由于年龄，性别，营养状态，慢性疾病和生活方式因素引起的基因表达的变异性是工人对职业暴露对呼吸道不良呼吸道影响的某些差异的基础。大规模的功能获得和功能丧失的基因组筛查可用于模拟人群中基因表达的固有多样性，并确定表达增加或下降的基因可能会改变职业暴露对不良影响的敏感性。为了评估这一假设，我们将使用人支气管上皮细胞作为职业支气管炎和IL-8产生的模型来使用五氧化聚氰化物（V2O5）作为炎症的替代物。在该提案的第一个具体目的中，我们将使用大规模的功能获得和功能丧失的基因组筛选来确定对钒诱导的气道炎症的敏感性的阳性修饰符。基因组筛选将在存在下炎性V2O5暴露的情况下确定哪些基因增加了表达的基因，增加了IL-8的产生。在第二个特定目的中，我们将使用大规模的功能获得和功能丧失的遗传筛查来确定对钒诱导的气道炎症的敏感性的负修饰符。基因组筛选将确定在存在炎症V2O5暴露的情况下，哪些基因降低了IL-8的产生。在最终的特定目的中，我们将使用其他钒反应性生物标志物来确认主要筛选的结果，并评估阳性和阴性修饰符的活性。通过这些特定目标，我们将完整地了解影响钒诱导的支气管炎的基因表达变化，并提供一种解决潜在的营养和生活方式因素的方法，这些因素可能会使工人或多或少容易受到呼吸作用的影响。在更大范围内，这种方法的发展对于整个环境健康界将是重要的，它提供了一种可概括的方法，该方法可以识别基因表达的变化，这是对许多职业和环境危害的敏感性的基础。项目叙述：保护个人免受职业暴露的不利影响，需要了解人群内部的变异性，并确定易感性增加的工人。一个人的DNA，饮食，慢性疾病（例如糖尿病）和生活方式因素都有助于个人工人之间的变异性。在该研究项目中，我们将开发一种方法来模仿单个工人所表达的基因数量以及这些差异是否会使工人或多或少易受职业暴露的不利影响。