# Molecular Mechanisms of Active Copper Transport

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $575,501

## Abstract

PROJECT SUMMARY
This proposal is to continue studies aimed to understand how absorption of different nutrients is coregulated
by small intestine in health and disease. Proper nutrient absorption by gastrointestinal tract is essential for
human health; dysregulation of GI function results in a broad spectrum of human disorders and in extreme
cases, death. We have discovered an unexpected and tight relationship between copper transport and fat
absorption in both healthy intestine and in the animal model of Wilson disease (WD). We demonstrated that
copper modulates maturation and trafficking of chylomicrons, the major carriers of dietary fat, and identified
specific steps in chylomicron processing that are sensitive to copper levels. Moreover, fatty acids regulate
trafficking and localization of Cu transporters in enterocytes, providing a feedback loop. We will now identify
the molecular mechanism of this co-regulation and examine how it is altered in human disease. In Specific
Aim 1, we will characterize the role of the copper transporters ATP7A and SLC31A1 in chylomicrons secretion
by examining the effects of their intracellular localization on ApoB trafficking, lipid content, and chylomicrons
secretion. Experiments in Specific Aim 2 will elucidate how intestinal ANKRD9 senses ATP levels and
facilitates ApoB and Slc31a1 trafficking in enterocytes; this will be done by characterizing the ANKRD9
macromolecular complexes and identifying ANKRD9 ATP-sensing site(s). Specific Aim 3 will determine how
Cu misbalance impacts metabolic status of human intestine in WD by characterizing the duodenal proteomes
of non-treated and chelator treated WD patients, as well as non-WD controls. Single cell nuclear sequencing
of human WD tissue will establish how Cu misbalance impacts cell speciation in intestine and the metabolic
state of human intestine.

## Key facts

- **NIH application ID:** 10881157
- **Project number:** 2R01DK071865-18
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SVETLANA LUTSENKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,501
- **Award type:** 2
- **Project period:** 2005-08-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881157

## Citation

> US National Institutes of Health, RePORTER application 10881157, Molecular Mechanisms of Active Copper Transport (2R01DK071865-18). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881157. Licensed CC0.

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