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

异生素受体介导环境对人类疾病的影响 项目概要/摘要： 这个R35提案旨在将我们目前的NIEHS资助项目合并为一个计划， 侧重于了解外源性受体在调节外源性物质代谢中的作用， 益生菌和这种调节对人类健康的影响。人类人口正在不断增长 患慢性疾病的风险，如纤维化、代谢综合征、酒精性肝病，以及 神经系统疾病环境因素，包括环境化学品，是主要的 这些慢性疾病的发病机制中的促成因素。因此，了解这些机制 环境化学物质改变人类生理和病理生理的机制将有助于设计 减轻环境化学品致病作用的治疗或预防策略。Xenobiotic 受体，包括异生物质核受体-雄烷X受体（PXR）和组成型雄烷 受体（CAR）和PAS结构域转录因子芳烃受体（AHR），最为人所知的是 它们在感受异生物化学物质和调节异生物代谢方面的功能。新出现的证据， 主要通过基因敲除小鼠的创建和表征以及内源性 配体，表明异生素受体也具有调节体内平衡的功能， 内生菌和影响病理生理学。我们的首要假设是，异生物素受体是 关键的环境化学传感转录因子介导的环境 对人类疾病和发病率的化学影响。从机制上讲，外源性受体影响 人类疾病的发病机制，通过调节代谢的外源性物质和内源性物质，在这两个 肝组织和肝外组织。我们认为，外源性受体是关键的环境 修饰剂整合了来自化学暴露的信号，以调节人体的许多方面， physiology.为了验证我们的假设，我们将组建一支经验丰富的团队， 遗传和药理学工具，跨学科方法，以及一系列 合作者和临床科学家全面定义的作用，异生素受体发挥， 环境影响的疾病，如纤维化、代谢综合征、酒精性肝病，以及 神经系统疾病通过了解这些途径，我们不仅可以了解环境-基因 相互作用和这些相互作用在人类疾病中的影响，而且还建立了异生素 受体及其靶酶和转运蛋白作为潜在的治疗靶点来管理这些人 疾病和发病率。从R35项目中获得的见解可用于设计干预措施 通过治疗或指导人类行为或人类行为来操纵这些途径的策略 以最有利于敏感人群的方式保护环境。在接下来的八年里， R35计划将给我们自由和力量，使我们在理解方面取得相当大的进步。 异生物素受体及其对人类健康的影响。作为首席研究员，我致力于 我将全部精力的55%投入到R35计划中，我现有的NIEHS资金将被合并 如果有资金的话我有信心我可以领导这个R35项目，因为我研究过异生物质， 二十年来，他展示了广阔的视野，并为我们的研究做出了开创性的贡献。 了解异生物质受体的毒理学和病理生理学功能。

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.