# Project 3 - Mechanisms of extra- and intra-cellular calcification

> **NIH NIH P01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $419,912

## Abstract

PROJECT 3 SUMMARY
Mechanisms of extra- and intra-cellular calcification. Recent findings from our laboratory showed that
extracellular calcification is an integral part of the hallmark lesions of age-related macular degeneration (AMD).
Calcified deposits rich in the calcium phosphate mineral hydroxyapatite (HAP) accumulate in the space under
the retinal pigment epithelium (RPE) in the back of the eye, where nutrient uptake and clearance of unwanted
material usually are exchanged between the blood circulation and the RPE cells. Inhibition of this exchange
process can lead to rapid progression to an end-stage disease characterized by irreversible visual loss. Apart
from AMD, sub-RPE deposit formation is also associated with other diseases such as Alzheimer’s disease
(AD). Based on recent findings, we proposed a new model for sub-RPE deposit initiation and growth where
calcification plays a pivotal role. We know from clinical and basic science studies that calcification, and the
associated interactions with proteins and lipids, have a negative effect on disease progression. We also
learned that understanding how different mineralization forms contribute to diseases is critical. However, we do
not yet know how calcification occurs and what intra- and extracellular molecules and pathways contribute to
mineral deposition in the sub-RPE space. This project will study the cellular and systemic contributors to
extracellular mislocalized (ectopic) calcification using a cellular model system we developed to study the
initiation and progression of the mineral-laden sub-RPE deposits. We will also develop a significantly improved,
new 3D microfluidic cell model to study calcification, as sub-RPE deposit formation, development and
progression of AMD and AD are linked to the choroidal endothelium and its degeneration. The results will be
validated using human postmortem eye tissues from patients with AMD and AD. The validation and the
experimental plan using the 2D and 3D cell culture systems will provide a robust foundation for developing new
intervention strategies centered on the calcification of the sub-RPE deposits. Apart from AMD and AD, these
treatment strategies will also be applicable for other diseases in which sub-RPE deposits play a role.

## Key facts

- **NIH application ID:** 10878735
- **Project number:** 5P01AG081167-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Imre Lengyel
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,912
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878735

## Citation

> US National Institutes of Health, RePORTER application 10878735, Project 3 - Mechanisms of extra- and intra-cellular calcification (5P01AG081167-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878735. Licensed CC0.

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