Application of Functional Genomics for Identifying Modifiers of Susceptibility

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、环境和生活方式因素都对人类反应的可变性有贡献。该项目的主要目标是开发一种创新方法，以确定职业照射敏感性的潜在改性剂。我们假设，由于年龄，性别，营养状况，慢性疾病和生活方式因素的基因表达的变异性的基础上的一些差异，工人的易感性，从职业暴露的不良呼吸道影响。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，并鉴定那些表达增加或减少可能改变对职业暴露不良反应易感性的基因。为了评估这一假设，我们将使用五氧化二钒（V2 O 5）治疗的人支气管上皮细胞作为职业性支气管炎和IL-8的生产作为炎症的替代模型。在本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鉴定对钒诱导的气道炎症敏感性的阳性修饰剂。基因组筛选将确定哪些基因表达改变，在亚炎性V2 O 5暴露的情况下增加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选来鉴定对钒诱导的气道炎症易感性的负调节剂。基因组筛选将确定哪些基因表达改变，在炎性V2 O 5暴露的存在下降低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，并使用其他钒响应生物标志物评估阳性和阴性修饰剂的活性。通过这些特定的目标，我们将收集影响钒诱导的支气管炎的基因表达变化的全貌，并提供一种方法来解决潜在的营养和生活方式因素，这些因素可能使工人或多或少地对呼吸系统的影响敏感。在更大的范围内，这种方法的发展将是显着的环境健康社区作为一个整体，提供了一个可推广的方法，可以识别基因表达的变化潜在的易感性众多的职业和环境危害。项目叙述：保护个人免受职业照射的不利影响，需要了解人口中的变异性，并确定易感性增加的工人。个体的DNA、饮食、慢性疾病（例如，糖尿病）和生活方式因素都导致了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个体工人表达的基因数量的差异，以及这些差异是否使工人更容易或更不容易受到职业暴露的不利影响。

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.