# Nuclear Receptor Dysfunction Reprograms Metabolism and Cellular Proliferation in Wilson's Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $305,576

## Abstract

PROJECT SUMMARY
 Wilson’s disease is an autosomal recessive disorder caused by mutations in the copper-transporting P-
type ATPase, ATP7b, resulting in excessive copper accumulation primarily in the liver and brain. Elevation of
free copper leads to oxidative stress and mitochondrial dysfunction, inflammation, steatosis, fibrosis, and
cirrhosis. Treatments for Wilson’s disease are limited to chelation or zinc therapies and often associated with
many side effects. Atp7b-/- mice exhibit hallmarks of the progressive liver pathology present in Wilson’s disease
patients. By using specific nuclear receptors expressed in the liver and intestine, we will address transcriptomic
and metabolomic changes to understand how copper reprograms the metabolic and cellular signaling pathways
in the liver of Atp7b-/- mice. The lack of well-defined molecular mechanisms for therapeutic targeting represents
a critical gap in our scientific understanding of liver disease. Our preliminary data in Atp7b-/- mice revealed
decreased metabolic nuclear receptor activity and target gene expression that dynamic changes in hepatic
metabolic composition. We also discovered that hepatic nodule formation in older Atp7b-/- mice is exacerbated
by deletion of PXR in Atp7b-/- mice. These findings suggest that reprogrammed metabolism and cell cycle
regulation contribute to the hepatic phenotype of Atp7b-/- mice, and overlap other chronic hepatic disorders.
Rationale: definition of molecular targets of Cu++ toxicity will provide novel therapeutic targets for WD treatment.
Our proposed studies will test the central hypothesis: Cu++-compromises PXR activities and promotes liver
dysfunction in Wilson’s disease.

## Key facts

- **NIH application ID:** 10832055
- **Project number:** 5R01DK129579-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Clavia Ruth Wooton-Kee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $305,576
- **Award type:** 5
- **Project period:** 2022-07-18 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832055

## Citation

> US National Institutes of Health, RePORTER application 10832055, Nuclear Receptor Dysfunction Reprograms Metabolism and Cellular Proliferation in Wilson's Disease (5R01DK129579-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10832055. Licensed CC0.

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