The PAS Sensor Family and Human Health

项目摘要 本R35提案旨在将两个R 01项目ES 005703和ES 020668合并为一个项目 一个程序，重点是了解环境如何影响人类健康，通过PAS 传感器家族的蛋白质。我们的方法是使用一个经验丰富的团队，广泛的 生物化学和基因试剂，跨学科的方法，以及一系列的专业知识， 合作者和临床科学家来定义PAS传感器在环境影响中发挥的作用， 疾病状态，如癌症、不孕症、肥胖症、糖尿病和炎症性肠病。我们 总体思路是，PAS传感器及其相关的环境信号，几乎 人类健康的每一个方面，通过他们的能力作为传感器的昼夜时间，氧气状态，化学 暴露和微生物组变化。我们认为，通过了解这些途径，我们不仅可以 通过环境以及环境与环境相互作用来识别重要基因，但是我们可以利用 这一信息，以制定干预战略，在许多环境的情况下，可能会导致 人类发病率。我们的愿景是通过Ah受体（AHR）的棱镜来了解这些途径 通过这些途径实际上是通过共同的伙伴相互作用的总体思想， 辅因子或配体。我们认为，从R35中获得的见解最终将有助于 干预策略，通过治疗或指导/改变人类行为来操纵这些途径， 以最有利于敏感人群的方式保护人类环境。在未来八 多年来，这一巩固的R35应该给我们的自由和权力，使我们在我们的相当大的进步， 了解PAS传感器以及它们如何影响人类健康。

PROJECT SUMMARY This R35 proposal is designed to consolidate two R01 programs, ES005703 and ES020668 into one program with an emphasis on understanding how environment influences human health through the PAS sensor family of proteins. Our approach is to use a highly experienced team, a broad spectrum of biochemical and genetic reagents, a transdisciplinary approach, and the expertise of an array of collaborators and clinician scientists to define the roles that PAS sensors play in environmentally influenced disease states such as cancer, infertility, obesity, diabetes and inflammatory bowel disease. Our overarching idea is that PAS sensors, and their related environmental signals, are impinging on almost every aspect of human health through their capacity as sensors of circadian time, oxygen status, chemical exposure and microbiome changes. We propose that by understanding these pathways, we can not only identify important gene by environment, and environment by environment interactions, but that we can use this information to develop intervention strategies in numerous environmental scenarios likely to be causing human morbidity. Our vision is to understand these pathways through the prism of the Ah receptor (AHR) and through the overarching idea that these pathways are in fact interacting through shared partners, cofactors or ligands. We propose that the insights gained from the R35 will ultimately be useful in intervention strategies to manipulate these pathways via therapeutics or to guide/modify human behavior or the human environment in a manner that is most beneficial to sensitive populations. Over the next eight years, this consolidated R35 should give us the freedom and power to make considerable advances in our understanding of PAS sensors and how they influence human health.