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

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $864,263

## Abstract

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 be...

## Key facts

- **NIH application ID:** 10411925
- **Project number:** 5R35ES030429-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Wen Xie
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $864,263
- **Award type:** 5
- **Project period:** 2019-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411925

## Citation

> US National Institutes of Health, RePORTER application 10411925, Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity (5R35ES030429-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10411925. Licensed CC0.

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