# Project 1 - Molecular structure and function

> **NIH NIH P01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $631,561

## Abstract

PROJECT 1 SUMMARY
Molecular structure and function. The ectopic accumulation of mineralized calcium-phosphate deposits in
the eye and brain is a hallmark of Age-Related Macular Degeneration (AMD) and Alzheimer’s Disease (AD). In
addition to inorganic components, such as hydroxyapatite (HAP), these deposits also contain lipids and
proteins of both blood and intracellular origin. The process of calcification is poorly understood, and it remains
unclear why some deposits progress to the disease state while others do not. It is also not clear if the
associated proteins are involved in the mineralization process, or if they deposit and accumulate on the already
pre-formed hydroxyapatite surface. Here, we address these important questions by comprehensive and
systematic investigation of the chemical, physical and structural properties of the molecular components
associated with calcified deposits, with particular focus on three validated constituents: the proteins vitronectin
(Vn), amyloid-b (Ab) and Tau. Vn is a blood glycoprotein with diverse functions in hemostasis, cell adhesion
and migration, innate immunity, tissue and bone remodeling. Recent studies have indicated that Vn binds both
soluble Ca2+ and solid HAP with chemical specificity and the T400M Vn variant is a major risk factor for AMD.
Ab and Tau are well known components of amyloid plaques in AD, but they are also found in calcification
deposits in the eye and the brain. First, we will investigate the role of these proteins in the calcification process
through fluorescence-based experiments and binding studies. Then, we will reconstitute proto-aggregates of
HAP, lipids and proteins to model pathological deposit formation in vitro. These aggregates will provide a
platform for assaying the functional roles of proteins and lipids in calcification and will aid the discovery of small
molecule and biomolecular inhibitors of calcification. And finally, we will use solid-state nuclear magnetic
resonance (NMR) spectroscopy to determine the structures of Vn, Tau and Ab within calcified deposits and to
describe the protein-mineral interactions that drive their assembly. This information will be essential for
understanding the molecular mechanism of calcification and, ultimately, for the development of new diagnostic
and therapeutic agents.

## Key facts

- **NIH application ID:** 10878726
- **Project number:** 5P01AG081167-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Francesca M Marassi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $631,561
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878726

## Citation

> US National Institutes of Health, RePORTER application 10878726, Project 1 - Molecular structure and function (5P01AG081167-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10878726. Licensed CC0.

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