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变异性，并确定易感性增加的工人。遗传、环境和生活方式因素都会导致人类反应的变异性。该项目的主要目标是开发一种创新的方法，以确定职业暴露易感性的潜在影响因素。我们假设，由于年龄、性别、营养状态、慢性病和生活方式因素导致的基因表达的差异性是工人对职业暴露的不良呼吸道影响易感性的一些差异的基础。大规模的功能获得和功能丧失基因组筛选可用于模拟人群中基因表达的固有多样性，并识别其表达增加或减少可能改变职业暴露不良影响的易感性的基因。为了评估这一假设，我们将使用五氧化二钒(V2O5)处理人支气管上皮细胞作为职业性支气管炎的模型，并将IL-8产生作为炎症的替代品。在这项建议的第一个具体目标中，我们将使用大规模功能获得和功能丧失基因组筛选来确定钒诱导的呼吸道炎症易感性的积极修饰物。基因组筛选将识别在亚炎性V2O5暴露下，哪些基因表达发生变化，增加IL-8的产生。在第二个具体目标中，我们将使用大规模功能获得和功能丧失基因筛查来确定钒诱导的呼吸道炎症易感性的负面修饰因素。基因组筛选将识别哪些基因在炎症性V2O5暴露时表达发生变化，减少IL-8的产生。在最终的具体目标中，我们将确认初步筛选的结果，并使用其他对钒反应的生物标志物来评估阳性和阴性修饰物的活性。通过这些具体目标，我们将汇集影响钒诱导支气管炎的基因表达变化的完整图景，并提供一种方法来解决可能使工人或多或少对呼吸影响易感的潜在营养和生活方式因素。在更大的范围内，这一方法的发展将对整个环境卫生社区具有重要意义，因为它提供了一种可推广的方法，可以识别导致对许多职业和环境危害的易感性的基因表达变化。项目简介：保护个人免受职业暴露的不利影响需要了解人群中的变异性，并确定易感性增加的工人。个体的DNA、饮食、慢性病(如糖尿病)和生活方式因素都会导致个体工人之间的差异。在这个研究项目中，我们将开发一种方法来模拟单个工人表达的基因数量的差异，以及这些差异是否会使工人更容易受到职业暴露的不利影响。