# Copper Homeostasis in Mammals

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $421,496

## Abstract

Copper (Cu) is an essential trace metal that is acquired from the diet and serves as a catalytic
co-factor for a wide variety of enzymatic reactions that play critical roles in life. Cu deficiency
leads to pathophysiological manifestations including impaired iron absorption, neutropenia,
cognitive defects, peripheral neuropathy and hypertrophic cardiomyopathy. Understanding the
mechanisms responsible for the accumulation of Cu in cells and tissues, the regulation of Cu
accumulation, and the consequences due to dysregulated Cu acquisition are important to
human health.
Ctr1 is the only known Cu+ importer in mammals and while Ctr1 plays an essential role in
dietary and peripheral Cu acquisition, embryonic development, cardiac function and normal
growth, little is known about the mechanisms that regulate Ctr1 activity. Ctr1 exists both as a
full-length protein and as a truncated form (tCtr1) lacking the extracellular Cu binding domain,
which has reduced Cu uptake activity. We identified cathepsin as a protease that carries out the
rate-limiting step in Ctr1 ecto-domain cleavage and demonstrated that this cleavage is
stimulated by the Ctr2 integral membrane protein. Among patients in a large cardiac
catheterization clinic cohort, we identified a single nucleotide polymorphism (SNP) in the human
Ctr1 gene that occurs predominantly in African Americans, resulting in hyper-cleavage of the
Ctr1 Cu-binding ecto-domain and decreased cellular Cu acquisition.
Here we detail experiments to test the hypothesis that Ctr1 ecto-domain cleavage,
through the cathepsin L/B proteases and Cu-responsive Ctr2 levels, is a critical
regulatory mechanism for mammalian Cu acquisition. Our experiments will identify new
components in mammalian Cu homeostasis, decipher a new mechanism for Cu-
dependent proteolysis, generate a new animal model and validate a link between a defect
in Ctr1 ecto-domain cleavage, Cu deficiency and hypertrophic cardiomyopathy in African
Americans.

## Key facts

- **NIH application ID:** 9854949
- **Project number:** 5R01DK074192-18
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Hiroaki Matsunami
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,496
- **Award type:** 5
- **Project period:** 2001-02-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854949

## Citation

> US National Institutes of Health, RePORTER application 9854949, Copper Homeostasis in Mammals (5R01DK074192-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854949. Licensed CC0.

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