# Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $511,395

## Abstract

Project Summary
Iron is an essential nutrient for humans, yet excess iron is toxic. As such, iron overload and iron deficiency
result in severe homeostatic perturbations. Iron overload is most frequently associated with hereditary
hemochromatosis (HH), which afflicts ~1:250 adults in the U.S. Tissue iron accumulation in patients with HH
leads to arthritis, osteoporosis, liver damage and cancer, cardiomyopathy, diabetes mellitus, and impotence.
HH results from impaired production of the iron-regulatory hormone hepcidin (HEPC) or as a result of
mutations in the HAMP gene (encoding HEPC). HEPC limits intestinal iron absorption. Moreover, reduced
HEPC synthesis underlies the iron loading that typifies disorders of ineffective erythropoiesis (e.g. β-
thalassemia intermedia [βTI]). In HH and βTI, intestinal iron absorption is thus excessive. This leads to
pathological iron overload since humans cannot excrete excess iron. Regulation of intestinal iron absorption is
thus critical to properly control body iron levels. Dietary iron exists primarily as inorganic (or nonheme) iron.
Ferric (Fe3+) nonheme iron is first reduced to Fe2+, imported into duodenal enterocytes by divalent metal-ion
transporter 1 (DMT1), exported by ferroportin 1 (FPN1) and oxidized for binding to transferrin. DMT1 is the
primary intestinal iron importer under basal conditions, but the relative contribution of DMT1 to iron
accumulation in HH and βTI is unknown. In Aim 1, we will thus test the hypothesis that DMT1 is required
for iron loading in mouse models of HH (HEPC KO) and βTI (Hbbd3th; with a mutated β major globin [Hbb-
b1]) gene. We will thus generate HEPC and Hbb-b1 KO mice that are also lacking intestinal DMT1. We further
hypothesize that decreasing DMT1 expression will prevent iron loading in HH and βTI. Accordingly, we have
developed ginger nanoparticle-derived lipid vectors (GNLVs) which can deliver functional DMT1 siRNA to the
mouse duodenum in vivo (~40% reduction in DMT1 expression). In Aim 2, this GNLV delivery system will be
tested for its ability to prevent iron loading in rodent models of HH and βTI. Furthermore, iron deficiency (ID) is
also common in the U.S., afflicting ~8 million young women, and 700,000 infants. ID frequently occurs when
absorption of dietary iron does not meet the body’s demand. ID most commonly occurs as a consequence of
rapid growth, pregnancy, menstrual blood loss, malabsorptive disorders, gastric bypass surgery and chronic
inflammation. ID symptoms include anemia, impaired cognition, decreased immune response, and fatigue.
During ID, DMT1 increases Cu transport into duodenal enterocytes and emerging data demonstrates that
copper is critical to support iron repletion during states of deficiency. The mechanism that transforms DMT1
into a copper transporter is, however, unknown. Aim 3 will thus test the hypothesis that the DMT1 protein is
post-translationally modified during iron deficiency, allowing Cu transport. Plausible alternative hypoth...

## Key facts

- **NIH application ID:** 9920132
- **Project number:** 5R01DK109717-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** James F. Collins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,395
- **Award type:** 5
- **Project period:** 2016-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920132

## Citation

> US National Institutes of Health, RePORTER application 9920132, Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport (5R01DK109717-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920132. Licensed CC0.

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