# Deciphering the Structures and Mechanisms of Metalloproteins Involved in Human Iron Homeostasis

> **NIH NIH R35** · PURDUE UNIVERSITY · 2024 · $379,754

## Abstract

Project Summary
Iron (Fe) is a redox-reactive metal that is essential for several critical physiological functions in the human body.
It plays an integral role in oxygen transport, DNA repair and synthesis, mitochondrial energy production, the
formation of myelin, the generation and metabolism of neurotransmitters, and the regulation of immune response
and defense mechanisms. The body needs to strictly maintain Fe levels as both deficiencies and excess can
result in severe health complications. A notable illustration of the consequences of Fe imbalance is ferroptosis,
an Fe-dependent form of programmed cell death that has become a focal point in cancer therapy. Furthermore,
Fe is acknowledged as a pivotal element in the progression of neurodegenerative diseases. Its accumulation
has been consistently observed in the parietal cortex, motor cortex, and hippocampus of brains impacted by
such disorders. Significant strides have been made in understanding the overall procedure of human Fe
homeostasis, and the principal components involved are relatively well-understood. However, the specific
molecular mechanisms governing Fe homeostasis remain obscure. This project will employ a multidisciplinary
approach to unravel the structures and mechanisms of metalloproteins integral to human Fe homeostasis from
the following perspectives: 1) Deciphering Fe transport through the membrane - Key components of the cellular
Fe-regulation system include the only known Fe exporter ferroportin (Fpn) and an extracellular ferroxidase
ceruloplasmin (Cp). Perturbation of the regulation is likely the direct cause of Fe accumulation in cells. This work
will study the synergistic effects between Fpn and Cp structurally and spectroscopically and clarify the
perturbation process; 2) Probing the interactome and transcriptome of iron regulatory proteins (IRPs) via
proximity labelling – IRPs are intracellular proteins that detect Fe concentrations and modulate the
expression/translation of Fe homeostasis-associated genes post-transcriptionally to maintain cellular iron
balance. This project will leverage proximity labeling to discern the interactome and transcriptome of IRP; 3)
Exploring the function of amyloid precursor protein (APP) - Amyloid plaques, aggregates of Aβ peptides, are
pathological hallmarks of Alzheimer's disease, originating from APP through secretase cleavage. However, the
biological role of APP remains enigmatic. Notably, APP mRNA contains an iron response element (IRE) in the
5'-UTR, hinting at a potential role in iron homeostasis as a ferroxidase, though definitive experimental evidence
is still pending. This portion of the project will investigate the biological functions of APP in relation to iron
homeostasis. In summary, the envisaged research is set to yield insights at the molecular level into Fe
homeostasis. This is foundational not just for acquiring an understanding of pivotal physiological functions, but it
also paves the way for pioneering therapeuti...

## Key facts

- **NIH application ID:** 10941253
- **Project number:** 1R35GM155016-01
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Shiliang Tian
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,754
- **Award type:** 1
- **Project period:** 2024-06-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941253

## Citation

> US National Institutes of Health, RePORTER application 10941253, Deciphering the Structures and Mechanisms of Metalloproteins Involved in Human Iron Homeostasis (1R35GM155016-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10941253. Licensed CC0.

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