The PAS Sensor Family and Human Health

项目总结 此R35提案旨在将ES005703和ES020668这两个R01计划整合为一个计划 计划，重点是了解环境如何通过PAS影响人类健康 蛋白质传感器家族。我们的方法是使用一支经验丰富的团队，广泛的 生化和遗传试剂，跨学科的方法，以及一系列 合作者和临床科学家确定PAS传感器在环境影响中所扮演的角色 疾病状态，如癌症、不孕不育、肥胖、糖尿病和炎症性肠病。我们的 最重要的想法是，PAS传感器及其相关的环境信号，正在撞击几乎 通过它们作为昼夜时间、氧气状态、化学物质的传感器的能力，人类健康的方方面面 暴露和微生物群的变化。我们认为，通过了解这些途径，我们不仅可以 通过环境识别重要的基因，以及环境与环境的交互作用，但我们可以使用 这些信息用于制定干预策略，在许多环境情景中可能会导致 人类发病率。我们的愿景是通过ah受体(Ahr)的棱镜来理解这些通路。 通过这些途径实际上是通过共享伙伴相互作用这一最重要的想法， 辅因子或配基。我们认为，从R35中获得的见解最终将在 干预策略，通过治疗学操纵这些通路，或引导/改变人类行为或 以对敏感人群最有利的方式保护人类环境。在接下来的八年里 几年来，这一合并的R35应该会给我们带来自由和力量，在我们的 了解PAS传感器及其对人类健康的影响。

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.