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

外源性受体介导环境对人类疾病和发病率的影响

基本信息

批准号：
10194495
负责人：
Wen Xie
金额：
$ 87.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10194495
关键词：
Alcoholic Liver Diseases Aryl Hydrocarbon Receptor Behavior Chemical Exposure Chemicals Chronic Disease Disease Environment Environmental Risk Factor Enzymes Exposure to Extrahepatic Fibrosis Freedom Functional disorder Funding Gene Expression Regulation Genetic Goals Grant Health Hepatic Homeostasis Human Intervention Knockout Mice Lead Ligands Mediating Mediator of activation protein Metabolic syndrome National Institute of Environmental Health Sciences Nuclear Receptors Outcome Pathogenesis Pathogenicity Pathway interactions Pharmacology Physiology Play Population Prevention strategy Principal Investigator Regulation Risk Role Scientist Seminal Signal Transduction Testing Therapeutic Tissues Toxicology Vision Xenobiotic Metabolism Xenobiotics constitutive androstane receptor design environmental chemical experience gene environment interaction human disease human morbidity insight knockout gene nervous system disorder pregnane X receptor programs receptor therapeutic target therapy design tool transcription factor

项目摘要

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.

标题：介导对人类疾病和发病率的环境影响时的异生物受体项目摘要/摘要：该R35提案旨在将我们当前的NIEHS资助的项目合并为一个计划专注于理解异生元受体在调节异种生物的代谢和内向生物及其在人类健康中的影响。人口正在越来越多患慢性疾病的风险，例如纤维化，代谢综合征，酒精性肝病和神经系统疾病。包括环境化学物质在内的环境因素是主要的这些慢性疾病的发病机理的因素。因此，了解机制环境化学物质修改人类生理学和病理生理学将有助于设计减轻环境化学物质的致病作用的治疗或预防策略。异生物受体，包括异生物核受体孕烯X受体（PXR）和组成型雄激素受体（CAR）和PAS结构域转录因子芳基烃受体（AHR）是最著名的它们在传感异生物化学物质和调节异种代谢方面的功能。新兴证据，主要通过基因基因敲除小鼠的创造和表征和内源性的鉴定配体，表明异生元受体在调节的稳态方面也具有功能内分生物和影响病理生理学。我们的总体假设是异生元受体是介导环境的关键环境化学感应转录因子化学对人类疾病和发病率的影响。从机械上讲，异种生物受体会影响通过调节异种生物和内生元的代谢，对人类疾病的发病机理肝和肝外组织。我们提出异种生物受体是关键的环境将信号从化学暴露到人类许多方面的调节的修饰符生理。为了检验我们的假设，我们将组建一个经验丰富的团队并采用广泛的范围遗传和药理学工具，跨学科方法以及一系列的专业知识合作者和临床医生科学家全面定义了异种生物受体在环境影响的疾病，例如纤维化，代谢综合征，酒精性肝病和神经系统疾病。通过理解这些途径，我们不仅可以理解环境基因这些相互作用及其在人类疾病中的相互作用的含义，但也建立了异种生物受体及其靶酶和转运蛋白作为管理这些人类的潜在治疗靶标疾病和发病率。从该R35程序中获得的见解可用于设计干预通过治疗学或指导人类行为或人类操纵这些途径的策略环境对敏感人群最有益。在接下来的八年中， R35计划将为我们提供自由和权力，使我们对异种生物受体及其如何影响人类健康。作为首席调查员，我致力于我全部努力的55％用于此R35计划，我所有现有的NIEHS资金都将合并如果获得资助，就可以进入这笔赠款。我有信心我可以领导这个R35程序，因为我已经学习了异生元受体已有二十年了，并且已经展示了广泛的视野，并为我们做出了开创性的贡献理解异种生物受体的毒理学和病理生理功能。