# Local hepcidin in the anterior segment: Physiological and pathological implications

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $201,250

## Abstract

ABSTRACT
Iron is an essential bio-metal, but requires tight regulation to minimize the generation of iron-catalyzed reactive
oxygen species (ROS). This is accomplished by hepcidin, a mainly hepatic peptide hormone that regulates
serum transferrin iron (Tf-iron) by downregulating ferroportin (Fpn), an iron export protein. The synthesis of local
hepcidin in the ciliary epithelial, corneal endothelial, and trabecular meshwork (TM) cells suggests autonomous
regulation of iron in the anterior segment, independent of the retina. However, hepcidin is upregulated by
cytokines as well, the latter signal superseding the signal from Tf-iron. This raises the concern of cytokine-
mediated upregulation of hepcidin, creating a toxic environment by increasing intracellular iron and ROS, known
contributors of toxicity in primary open angle glaucoma (POAG) and other ocular conditions. Pertinent to this
application is TGFβ2, a cytokine implicated in POAG. Data from my laboratory show that biologically active
TGFβ2 upregulates hepcidin in primary human TM cells and ex-vivo human organ culture perfusion model of
POAG. Remarkably, hepcidin upregulates full-length (FL) and biologically active TGFβ2, the latter probably
through ROS, forming a self-sustained feed-forward loop that is disrupted by heparin, a hepcidin antagonist, and
N-acetyl carnosine, an antioxidant. Based on these observations, we hypothesize that the anterior segment
maintains autonomous regulation of iron by locally synthesized hepcidin, and cytokine-mediated upregulation of
local hepcidin forms a self-sustained feed-forward loop that is disrupted by hepcidin antagonists and Fpn
stabilizing agents. This hypothesis will be tested in three specific aims. In Aim 1,autonomous regulation of iron
by the anterior segment will be explored in wild-type (wt) C57BL/6 and Balb/c mice at steady state and after
systemic iron overload that is known to cause retinal iron accumulation. Transport of serum iron across the blood-
aqueous barrier, and from the retina to the aqueous humor (AH) will be determinedin the absence or presence
of exogenous synthetic hepcidin in the AH. The role of local hepcidin in corneal endothelial cells in regulating
iron exchange between the AH and the cornea will be determined in the human corneal cup ex-vivo model. In
Aim 2,
levels of FL and bioactive TGFβ2 will be determined in hepcidin knock-out (hepc-/-) and littermate hepc+/+
controls at steady state, and after over-expressing FL TGFβ2 to evaluate whether absence of hepcidin and iron-
mediated ROS decreases bioactive TGFβ2 and IOP
. In addition, levels of hepcidin, Tf-iron, and TGFβ2 will be
determined in the human AH of POAG cases and cataract controls collected at surgery. In Aim 3, ex-vivo human
anterior segment organ culture perfusion model will be used to evaluate the efficacy of FDA approved Fpn
stabilizing agent fursultiamine in reducing intracellular iron, ROS, and bioactive TGFβ2-mediated
increase in
IOP
. Successful completi...

## Key facts

- **NIH application ID:** 10370658
- **Project number:** 1R21EY032694-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Neena Singh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $201,250
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370658

## Citation

> US National Institutes of Health, RePORTER application 10370658, Local hepcidin in the anterior segment: Physiological and pathological implications (1R21EY032694-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10370658. Licensed CC0.

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