# Integrative Analysis of Wilson's Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $537,198

## Abstract

PROJECT SUMMARY
The long-term goal of this project is to understand the fundamental mechanisms that regulate human copper
(Cu) homeostasis in the central nervous system. Cu is essential for numerous physiologic processes, including
myelination of neurons, immune response, catecholamines balance, mitochondria respiration, and protection
against oxygen radicals. Disrupted Cu homeostasis causes or significantly contributes to the pathogenesis of
several neurodegenerative disorders including Menkes disease, Wilson disease, MEDNIK syndrome, and
Alzheimer's disease. The molecular mechanisms that govern Cu homeostasis in most cells of the central
nervous system, especially during metabolic changes, are greatly understudied and poorly understood. This
project will feel the information gap by characterizing the biochemical mechanisms of Cu transport and
utilization in noradrenergic neurons (NEN) of locus coeruleus. The experiments will determine specific roles of
the two Cu-transporting ATPases (Cu-ATPase) ATP7A and ATP7B in the maintenance of the cytosolic Cu
balance in these neurons and in activation of dopamine-β-hydroxylase (DBH), the key enzyme involved in
biosynthesis of norepinephrine. The studies will also characterize the NEN-specific regulatory mechanisms that
coordinate the Cu-ATPases activity with DBH secretion. The research program has three specific aims.
Experiments under Aim 1 will elucidate how ATP7A, ATP7B and the Cu chaperone Atox1 work together to
maintain Cu homeostasis in noradrenergic neurons. Studies under Aim 2 will determine the role of Cu-
ATPases ATP7A and ATP7B in activation and secretion of dopamine-β-hydroxylase (DBH), and Aim 3 will
characterize the novel feedback pathway by investigating how Cu counteracts the inhibitory effect of NE on
DBH secretion. The results will help to develop new mechanistic paradigms of Cu homeostasis in the brain,
contribute to understanding of Wilson disease pathogenesis, and, ultimately, help to design better treatments
for disorders of Cu misbalance.

## Key facts

- **NIH application ID:** 9838231
- **Project number:** 5R01GM101502-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SVETLANA LUTSENKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,198
- **Award type:** 5
- **Project period:** 2012-08-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838231

## Citation

> US National Institutes of Health, RePORTER application 9838231, Integrative Analysis of Wilson's Disease (5R01GM101502-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838231. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*