# ZIP Proteins and Iron Metabolism

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2024 · $225,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The iron overload disorder hereditary hemochromatosis is an endocrine liver disease that results from an inability
to produce sufficient amounts of hepcidin, the iron-regulatory hormone produced by the liver. In
hemochromatosis, increased absorption of dietary iron leads to the appearance of plasma non-transferrin-bound
iron (NTBI), which is taken up by various tissues and cells leading to tissue iron overload and related pathology.
Plasma NTBI is also commonly seen in the hematologic disease beta-thalassemia major, an inherited blood
disorder that requires regular blood transfusions, which over time result in iron overload. Although NTBI is the
major contributor to tissue iron loading, our understanding of the molecular mechanisms that mediate NTBI
uptake is incomplete. The primary long-term objective of this proposal is to define the proteins that transport iron
into various tissues and cells, particularly those affected by iron-overload related pathology. Our central
hypothesis is that the membrane transport proteins SLC39A14 (ZIP14) and (ZIP8) participate in iron homeostasis
and NTBI uptake. In the previous funding period, we generated a variety of conditional and double-knockout
mouse models, which enabled us to find that SLC39A14 is required for iron loading of the heart in a mouse
model of hemochromatosis and that SLC39A8 participates in systemic iron recycling, iron uptake by the lung,
and iron accumulation by the kidney and brain. We also demonstrated that reducing SLC39A14 expression
(pharmacologically or genetically) combined with iron chelation is more effective than iron chelation alone in
decreasing hepatic, cardiac, and total body iron in a mouse model of hemochromatosis. The current project will
investigate the efficacy of pharmacological approaches to reduce tissue-specific SLC39A14 expression in mouse
models of beta thalassemia and hemochromatosis. Another substantial focus will be to characterize the
molecular mechanisms of iron uptake and accumulation by the kidney, as renal iron accumulation and associated
adverse effects have been documented in a variety of disorders, including acute kidney injury, chronic kidney
disease, and diabetic nephropathy.

## Key facts

- **NIH application ID:** 11159300
- **Project number:** 2R56DK080706-15
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Mitchell D Knutson
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $225,000
- **Award type:** 2
- **Project period:** 2009-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11159300

## Citation

> US National Institutes of Health, RePORTER application 11159300, ZIP Proteins and Iron Metabolism (2R56DK080706-15). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/11159300. Licensed CC0.

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