# Identifying the Role of Fibroblast-Macrophage Crosstalk in Aortic Valve Stenosis Sexual Dimorphism

> **NIH NIH F32** · UNIVERSITY OF COLORADO · 2024 · $74,284

## Abstract

PROJECT SUMMARY/ABSTRACT
 Thirteen percent of adults over 75 suffer from aortic valve stenosis (AVS), a progressive disease that leads
to aberrant collagen deposition, leaflet stiffening, and eventual valve calcification at late stages. As it stands,
surgical or transcatheter valve replacement is the only treatment option for severe AVS and is limited in durability
and can require indefinite anticoagulation therapy. AVS is also sexually dimorphic with men having a two-fold
higher risk for developing direct calcification, whereas women with equal disease severity tend to have more
valvular fibrosis prior to calcification. The molecular mechanisms underlying sexual dimorphism in AVS
progression remain poorly understood, but growing evidence suggests AVS is an inflammation-dependent
disease. Recent studies have focused on the role that infiltrating immune cells such as macrophages play in
AVS, with a growing appreciation that men and women undergo different immune responses and show
differences in compositions of inflammatory cytokines. Combined, these observations suggest not only the need
for alternative treatments for AVS (e.g., pharmaceutical therapies), but also the opportunity to develop
personalized treatments based on sex and inflammatory state. Based on the extant evidence, we propose to
investigate the role of inflammation in sex-specific valve disease progression. We hypothesize that AVS sexual
dimorphism is perpetuated by: 1) sex differences in valve cell secreted factors promoting differential polarization
of macrophages, 2) differences in infiltration behavior of male and female macrophages, and 3) direct
macrophage-valve cell contact eliciting distinct phenotypic differentiation dependent upon sex, leading to the
formation of a pro-fibrotic or pro-calcific niche. We will test these hypotheses with the following specific aims (1)
Delineate how secreted factors from valve cells effect macrophage phenotype and vice versa in a sex-dependent
manner, (2) Elucidate sex-specific differences in AVS disease initiation within an in vitro 3D co-culture model.
The applicant, Dr. Alex Khang, will work with sponsor, Dr. Kristi S. Anseth, collaborating investigators with
expertise in immunology (Dr. Laurel Hind) and sex-specific differences (Dr. Leslie Leinwand), and microscopy
consultant Dr. Joseph Dragavon to carry out the experimental studies. All studies will be performed at the
University of Colorado Boulder. All members of the research team and the required equipment for the proposed
research are housed in the same building (Jennie Smoly Caruthers Biotechnology Building, JSCBB) which will
facilitate constant interactions as well as frequent opportunities for mentorship, while eliminating logistical issues.
The JSCBB also houses numerous faculty that are domain-experts and word-leaders in their respective field
who Dr. Khang will interact with frequently at local seminars and events. During the funding period, Dr. Khang
will gain expertise in en...

## Key facts

- **NIH application ID:** 10998691
- **Project number:** 1F32HL176073-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Alex Khang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998691

## Citation

> US National Institutes of Health, RePORTER application 10998691, Identifying the Role of Fibroblast-Macrophage Crosstalk in Aortic Valve Stenosis Sexual Dimorphism (1F32HL176073-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10998691. Licensed CC0.

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