Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity

异种生物受体在调节环境对人类疾病和发病率影响中的作用 项目摘要/摘要： 这份R35提案旨在将我们目前由NIEHS资助的项目整合为一个计划，其中 重点了解外源受体在调节外源物质代谢中的作用 内生菌和这一规定对人类健康的影响。人口正处于增长阶段。 患慢性疾病的风险，如纤维化、代谢综合征、酒精性肝病和 神经紊乱。环境因素，包括环境化学品，是主要的 在这些慢性疾病的发病机制中的促成因素。因此，理解这些机制 环境化学物质通过改变人体生理和病理生理学将有助于设计 减轻环境化学品致病作用的治疗或预防战略。异种生物 受体，包括异源核受体孕烷X受体(PXR)和构成雄烷 受体(CAR)和PAS结构域转录因子芳香烃受体(AHR)，最为人所知的是 它们在感知外源化学物质和调节外源代谢方面发挥着重要作用。新出现的证据， 主要通过基因敲除小鼠的建立和鉴定以及内源基因的鉴定 配体，提示外源受体也具有调节细胞内环境平衡的功能。 内生菌和影响病理生理学。我们的主要假设是外源受体是 关键的环境化学传感转录因子调节环境 化学物质对人类疾病和发病率的影响。从机制上讲，异种受体影响着 外源和内源物质在人体内代谢的调节与疾病发病机制的研究 肝组织和肝外组织。我们认为异种受体在环境中起着关键作用。 将化学暴露的信号整合到人类许多方面的调节的修饰物 生理学。为了验证我们的假设，我们将组建一支经验丰富的团队，并使用广泛的 遗传和药理学工具、跨学科方法和一系列 合作者和临床科学家全面定义外源受体在 环境影响的疾病，如纤维化、代谢综合征、酒精性肝病以及 神经紊乱。通过了解这些途径，我们不能只了解环境基因 相互作用和这些相互作用在人类疾病中的含义，但也建立了异种生物 受体及其靶向酶和转运体作为潜在的治疗靶点来管理这些人类 疾病和发病率。从R35计划中获得的见解可用于设计干预措施 通过治疗学操纵这些通路的策略，或指导人类行为或人类 以对敏感人群最有利的方式保护环境。在接下来的八年里，这 R35计划将给我们自由和力量，让我们在理解 异种生物受体及其对人类健康的影响。作为首席调查员，我致力于 将我55%的全部精力投入到R35计划中，我现有的所有NIEHS资金将得到整合 如果有资金的话就加入到这笔赠款中。我有信心领导这个R35项目，因为我研究过异生生物 受体已有二十年的历史，展示了广阔的视野，并为我们的 了解异种受体的毒理和病理生理功能。

Title: Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity Project Summary/Abstract: This R35 proposal is designed to consolidate our current NIEHS funded projects into one program with the focus on understanding the role of xenobiotic receptors in regulating the metabolism of xenobiotics and endobiotics and the implications of this regulation in human health. The human population is at an increasing risk of developing chronic diseases, such as fibrosis, metabolic syndrome, alcoholic liver disease, and neurologic disorders. Environmental factors, including environmental chemicals, are among the major contributing factors in the pathogenesis of these chronic diseases. As such, understanding the mechanisms by which environmental chemicals modify human physiology and pathophysiology will help to design therapeutic or preventive strategies to mitigate the pathogenic effect of environmental chemicals. Xenobiotic receptors, including the xenobiotic nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and the PAS domain transcriptional factor aryl hydrocarbon receptor (AHR), are best known for their functions in sensing xenobiotic chemicals and regulating xenobiotic metabolism. Emerging evidence, mainly through the creation and characterization of gene knockout mice and identification of endogenous ligands, suggests that the xenobiotic receptors also have functions in regulating the homeostasis of endobiotics and impacting pathophysiology. Our overarching hypothesis is that xenobiotic receptors are critical environmental chemical-sensing transcriptional factors that mediate the environmental chemical effects on human disease and morbidity. Mechanistically, xenobiotic receptors impact the pathogenesis of human diseases by regulating the metabolism of xenobiotics and endobiotics in both the hepatic and extrahepatic tissues. We propose that the xenobiotic receptors are pivotal environmental modifiers that integrate signals from chemical exposures to the regulation of many aspects of human physiology. To test our hypothesis, we will assemble a highly experienced team and employ a broad spectrum of genetic and pharmacological tools, transdisciplinary approaches, and the expertise of an array of collaborators and clinician scientists to comprehensively define the roles that xenobiotic receptors play in environmentally influenced diseases, such as fibrosis, metabolic syndrome, alcoholic liver disease, and neurologic disorders. By understanding these pathways, we cannot only understand the environment-gene interactions and the implications of these interactions in human diseases, but also establish xenobiotic receptors and their target enzymes and transporters as potential therapeutic targets to manage these human diseases and morbidity. The insights gained from this R35 program can be used to design intervention strategies to manipulate these pathways via therapeutics or to guide human behavior or the human environment in a manner that is most beneficial to the sensitive populations. Over the next eight years, this R35 program will give us the freedom and power to make considerable advances in our understanding of xenobiotic receptors and how they influence human health. As the Principal Investigator, I am committed to devote 55% of my total effort to this R35 program, and all of my existing NIEHS funding will be consolidated into this grant if funded. I am confident that I can lead this R35 program, because I have studied xenobiotic receptors for two decades and have demonstrated a broad vision and made seminal contributions to our understanding of the toxicological and pathophysiological functions of xenobiotic receptors.