# Engineered Models of Diseased Heart Valves to Study Sex Bias in Disease Progression

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $380,900

## Abstract

PROJECT SUMMARY
Calcific aortic valve disease (CAVD) is a prevalent condition for which the only approved treatment is surgical
valve replacement. Age and male sex are the dominant risk factors for developing this disease, which is
characterized in its earliest stages by a change in extracellular matrix (ECM) composition. Moreover, recent
evidence has indicated that the pathogenesis of CAVD in men may differ from that in women.
We hypothesize that male and female valvular cells exhibit differential responsiveness to their
microenvironment (i.e., ECM) and pathological cues (i.e., co-morbidities or risk factors), resulting in divergent
disease trajectories for men and women. While clinical and animal studies can provide snapshots of disease
progression, they do not permit the tailorability and high throughput needed to investigate this question and
precisely monitor the specific cell/microenvironment/stimulus interactions that may yield mechanistic
information about disease progression. Thus, we propose to develop in vitro disease-mimicking environments.
Specifically, we will use novel tissue engineering and ECM-editing methods to create 3D engineered
environments that recapitulate key features of the valve ECM and valvular interstitial cell phenotype at various
stages of CAVD, and then use these scaffolds/tissues to examine disease progression upon exposure to risk
factors and pathological stimuli. These defined, controlled environments will enable hypothesis testing that is
impossible in humans and very difficult or not practical in animals, and will allow a prospective etiological
investigation of sex bias in events that contribute to CAVD through execution of the following Aims:
Aim 1: Construct engineered models that represent the valve microenvironment at different stages of disease.
Aim 2: Investigate sex bias in the onset of inflammation using engineered models of CAVD.
Aim 3: Investigate sex bias in the progression of fibrosis using engineered models of CAVD.
Aim 4: Design organ cultures to validate engineered disease models and probe mechanism.
This work has the potential to identify specific valve changes that can inform the design of sex- or stage-
specific intervention strategies to reduce CAVD risk or progression and sets the stage for future work to
improve CAVD prevention and treatment. We will make these advancements through our implementation of
transformative approaches and tools to study ECM (patho)biology, which can also be readily applied to other
cardiovascular (or non-cardiovascular tissues).

## Key facts

- **NIH application ID:** 9841985
- **Project number:** 5R01HL141181-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** KRISTYN S MASTERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,900
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841985

## Citation

> US National Institutes of Health, RePORTER application 9841985, Engineered Models of Diseased Heart Valves to Study Sex Bias in Disease Progression (5R01HL141181-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9841985. Licensed CC0.

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