GENE BY ENVIRONMENT INTERACTION IN LPS EXPOSURE

哮喘被认为是一种慢性炎症性疾病。它涉及外源[环境]和内源[遗传]因素之间的复杂相互作用。这项研究的长期目标是了解环境暴露影响哮喘发展的分子机制。CD14是内毒素和其他细菌“危险”信号的主要受体。本课题组在CD14基因启动子区域发现了5个多态(转录起始点-159、-809、-1145、-1359、-1619)。我们推测CD14基因启动子区域的多态可能改变CD14的表达，进而改变个体对脂多糖暴露的敏感性。这项建议是为了分子流行病学领域的职业发展，该领域旨在通过研究和教学培训将流行病学和分子生物学结合起来。本项目的研究目的是：(1)确定对内毒素吸入的急性反应与CD14基因遗传多态之间的关系；(2)阐明CD14基因多态在人群中对CD14基因转录的特殊作用；(3)将个体的CD14转录活性与血清CD14转录活性和CD14膜CD14积累量作为CD14启动子基因型和推测的单倍型的函数联系起来。这笔资助的教学目标是(1)完成流行病学硕士学位；(2)开发和教授为期16周的分子流行病学课程；(3)加入国际分子流行病学特别工作组；(4)参加关于分子流行病学、遗传流行病学、职业暴露和/或呼吸系统疾病的会议/短期课程。完成这些研究和教学目标将使候选人成为分子流行病学领域的独立研究人员，重点是影响呼吸道疾病的基因的分子生物学研究。

Asthma is considered a chronic inflammatory disease. It involves complex interactions between exogenous [environmental] and endogenous [genetic] factors. The long-term objective of this research is to understand the molecular mechanisms by which environmental exposures can influence the development of asthma. CD 14 is the main receptor for LPS and other bacterial "danger" signals. Our group has found five polymorphisms in the promoter region of the CD14 gene (positions -159, -809, -1145, -1359, -1619 from the transcription start site). We hypothesize that polymorphisms in the promoter region of the CD 14 gene may alter expression of CD 14, and this in turn could alter an individuals sensitivity to LPS exposure. This proposal is for career development in the area of Molecular Epidemiology, which is designed to integrate Epidemiology and Molecular Biology through research and didactic training. The research aims of this project are (1) to determine the association between an acute response to LPS inhalation and genetic polymorphisms in the CD 14 gene; (2) to elucidate the specific role of the CD 14 polymorphisms in CD 14 gene transcription in the context of a population; and (3) to associate an individual's CD 14 transcriptional activity with serum CD 14 and membrane CD 14 accumulation as a function of CD 14 promoter genotypes and putative haplotypes. The didactic goals of this grant are (1) to complete a Masters degree in Epidemiology; (2) to develop and teach a 16-week course on Molecular Epidemiology; (3) to join the International Molecular Epidemiology Task Force; and (4) to attend conferences/short courses on Molecular Epidemiology, Genetic Epidemiology, Occupational Exposures and/or Respiratory Disease. Completion of these research and, didactic goals will allow the candidate to become an independent researcher in the field of Molecular Epidemiology, with particular emphasis on the study of the molecular biology of genes that influence respiratory diseases.