# Endothelial-Interstitial Interactions in Aortic Valve Homeostasis and Disease

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $497,109

## Abstract

Project Summary
Nearly 4 million Americans over 65 are living with calcific aortic valve disease (CAVD). CAVD pathogenesis is
an active biological process that is untreatable by cholesterol metabolism modifying agents. There are
currently no successful biological targets or therapeutic agents that specifically target CAVD. Aortic valve cusp
homeostasis and pathogenesis is regulated by complex and poorly understood interactions between resident
surface valve endothelial cells (VEC) and underlying valve interstitial cell (VIC). While almost all research has
focused on VIC, which cannot be isolated from VEC that surround them and faithfully reveal the biology of
aortic valves and pathobiology of CAVD, this research project aims to unravel the roles of VIC, VEC and their
interactions, at cell and molecule levels, for valve homeostasis and CAVD. Our preliminary data using new
valve lineage specific genetic animal models show that activation of NFκB (a master gene mediating
inflammation) in VEC and VIC, or inaction of Notch1 (a major regulator of cell fate and behavior) in VEC only
results in CAVD in mice. Further, our innovative 3D in vitro culture of VEC identifies that NFκB activation in
VEC promotes VEC undergo endothelial-to-mesenchymal transformation and generate a novel mesenchymal
progenitor T-VIC that calcifies matrix. These exciting new results motivate the hypothesis that NFκB-Notch1
control valve homeostasis and CAVD pathogenesis via prevention or generation of these T-VIC. This proposal
will be tested in three Specific Aims. First we will elucidate the role of Notch-NFkB in VEC homeostasis and
CAVD related pathogenesis (Aim 1). Then we will elucidate how T-VIC affect VEC and/or VIC phenotypes in
3D co-culture in novel CAVD-related conditions (Aim 2). Aim 3 will evaluate the efficacy of NFκB-Notch1
signaling rebalancing on CAVD initiation and progression in vivo via reduction of T-VIC. The completion of this
project will generate significant information regarding intercellular regulation of aortic valve homeostasis and
the CAVD pathogenic process. By revealing the unique phenotypic signatures of participation VEC and VIC,
our study will also identify and motivated new molecular candidates that specifically target the cell specific
characteristics of the CAVD process for potential diagnostic and therapeutic benefit.

## Key facts

- **NIH application ID:** 9978112
- **Project number:** 5R01HL143247-03
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Jonathan Talbot Butcher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,109
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978112

## Citation

> US National Institutes of Health, RePORTER application 9978112, Endothelial-Interstitial Interactions in Aortic Valve Homeostasis and Disease (5R01HL143247-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978112. Licensed CC0.

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