# Structure-Function Relationship of the Extracellular Matrix Proteome in Congenital Aortic Valve Stenosis

> **NIH NIH F31** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $34,797

## Abstract

Project Summary
This proposal focuses on novel molecular mechanisms underlying aortic valve (AV) development in health and
disease. The preliminary data presented in this proposal shows that extracellular matrix (ECM) proteins play a
key role in healthy AV structure and function during development, and when dysregulated contribute AV
thickening and dysfunction (i.e., congenital aortic valve stenosis, CAVS). Specifically, we have identified collagen
type proteins to be particularly dysregulated along with a collagen stabilizing post-translational modification,
hydroxylation of prolines (HYP). Identifying the molecular mechanisms behind collagen stabilization during
development and the rapid collagen dysregulation seen in this valve disease are the basis for this proposal.
CAVS will account for 10% of all congenital heart defects, which affect 1 in every 150 people. CAVS progresses
as valvular thickening that narrows the aortic opening, leading to restricted blood flow, left ventricular hypertrophy
and eventual heart failure. Despite the clinical significance of this disease, patients must “watch and wait” until
surgical valve replacement and repair is necessary, as currently no pharmacotherapeutics exist. There are two
distinct CAVS subtypes: i) adult fibrocalcific, accounting for 90% of cases in which the end-stage requiring valve
replacement is valve calcification, and ii) pediatric, accounting for the remaining 10%, where end-stage is rapid
and excessive ECM deposition at a young age, with no calcification. In pediatric cases, bioengineered valve
replacement options are not suitable, creating a critical need for pharmacotherapeutic target development.
The proposed research capitalizes on a unique cohort of clinically defined, biorepository-obtained, human
pediatric CAVS tissue samples and age matched normal samples. It is our central hypothesis that reduced
collagen HYP modifications contributes to rapid ECM dysregulation in pediatric end-stage CAVS. We will
address our hypothesis through the following Specific Aims: Aim 1 will define the spatial localization of collagen
HYP sequences relative to histopathology-defined collagen structural signatures in AV development and
pathologies. State-of-the-art imaging mass spectrometry (IMS) methodologies, coupled with previously acquired
peptides databases, will report expression levels and spatial localization of HYP modified collagen peptides,
across a clinically and histopatholgoically well-defined cohort of human AV tissues. Aim 2 will determine the
local ECM “niche” of differentially activated valvular interstitial cells. Immunohistological staining of VICs will be
coupled with IMS to profile corresponding ECM “niches” of these cells. This aim will identify the cell-mediated
mechanism to the etiology of pediatric CAVS. Understanding the molecular mechanisms driving collagen
organization and deposition in CAVS is key to identifying biomarkers and pharmacotherapeutic targets that may
halt progression...

## Key facts

- **NIH application ID:** 10146048
- **Project number:** 1F31HL156524-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Cassandra Lucille Clift
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,797
- **Award type:** 1
- **Project period:** 2021-01-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146048

## Citation

> US National Institutes of Health, RePORTER application 10146048, Structure-Function Relationship of the Extracellular Matrix Proteome in Congenital Aortic Valve Stenosis (1F31HL156524-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146048. Licensed CC0.

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