# Propagation and Resolution of Injury in Calcific Aortic Valve Disease

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $443,584

## Abstract

Project Summary
Calcific aortic valve stenosis (CAVS) can be viewed as the end-stage of prolonged persistent injury in valve
tissue. Isolated valve interstitial cells (VICs), CAVS-prone mice, and humans with subclinical aortic valve
disease all demonstrate a propensity for propagation of injury in valve tissue, even after the initiating cause is
rectified. The goals of this proposal are understand mechanisms, and to identify therapeutic strategies with the
potential to inhibit or reverse propagation of injury in valve tissue. Early aortic valve disease entails thickening
and stiffening of valve cusps, and disruption of laminar shear at the blood-valve interface. The proposal will
address the hypothesis that tissue responses to altered mechanical forces may propagate a pattern of injury in
the aortic valve. Therefore, experiments proposed for Aim 1 will study modulation of signaling by the
mechano-responsive calcium channel, TRPV4, as a means to inhibit propagation of injury. In other disease
states, persistent tissue injury is characterized by sustained actions of mediators of inflammation, which may
be amenable to inhibition by specialized pro-resolving mediators (SPMs). New preliminary data indicate that
two SPMs are expressed in aortic valve cells, and that their expression is altered by CAVS-relevant conditions.
Experiments proposed for Aim 2 will study the impact of modulation of those two SPMs, annexin A1 and
chemokine-like receptor-1, upon propagation of injury in aortic valve cells. Both Aims will be pursued using
VICs grown on matrix with mechanical properties that can be manipulated to resemble properties of aortic
valves. Both Aims will be pursued using a mouse model that consistently develops CAVS, and which reaches
a state where amelioration of the initiating cause of CAVS no longer inhibits disease progression. These new
areas of research in aortic valve disease hold promise for translation to effective therapies for CAVS.

## Key facts

- **NIH application ID:** 10452547
- **Project number:** 5R01HL142935-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** ROBERT M WEISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $443,584
- **Award type:** 5
- **Project period:** 2018-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452547

## Citation

> US National Institutes of Health, RePORTER application 10452547, Propagation and Resolution of Injury in Calcific Aortic Valve Disease (5R01HL142935-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10452547. Licensed CC0.

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