# Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $782,105

## Abstract

Project Summary/Abstract
Hypertrophic cardiomyopathy (HCM) is a common familial cardiovascular disorder viewed as a genetic disease
of the sarcomere, since most mutations occur in genes that encode sarcomere/cytoskeletal proteins. Despite
decades of basic and clinical research, there are critical gaps in our knowledge concerning how defective
biophysical signals in the myocyte influence the function of other cellular compartments of the heart during the
clinical course of this disorder. We have reported that early interventions aimed at normalizing myofilament
properties only partially prevent HCM progression. Moreover, removal of the triggering mutation does not
always reverse progression. In experiments proposed here, we test the overall hypothesis that critical, but
treatable, maladaptive modifications in the vascular/endothelial compartment occur early and in parallel with
changes in myofilament properties in the progression of HCM linked to thin filament mutations triggering
different biophysical and biochemical signals. Preliminary data strongly support a role for and a need to
investigate vascular remodeling and endothelial dysfunction that exacerbate symptomatic HCM. Novel data
support our focus on HIPPO/YAP/TAZ signaling with emphasis on protective effects of sphingsine-1-phosphate
receptor (S1PR) signaling, which is common to the endothelium (EC) and myocytes (CM). Our aims are as
follows: Aim 1. Determine the decline in coronary function, changes in vascular remodeling and mechano-
sensing in HCM linked to mutationsTnT-R92Q and Tm-E180G with different signaling in progression to HCM.
Aim 2. Establish whether restoration of the endothelial HIPPO pathway is sufficient to impede HCM
progression. Evidence provided here for a role of EC HIPPO/YAP/TAZ signaling in HCM progression demands
an investigation of the consequences of its regulation, and whether therapeutic interventions modify HIPPO
signaling. Aim 3. Evaluate the microenvironmental signals responsible for HIPPO pathway dysregulation and
co-translation expression of activated YAP/TAZ protective mediators in HCM. Our approach includes
determination of the time course of changes in coronary flow velocity, vascular/endothelial histology, and
mechano-sensing through key components of the HIPPO pathway, with changes in cardiac function and the
myofilaments Ca2+-response during HCM progression. We will treat mouse models early in HCM progression
with S1PR agonists, and small molecule inhibitors to normalize myofilament Ca2+ sensitivity and tension to
examine whether they restore EC HIPPO pathway and angiogenic signaling. We will identity EC and CM
specific disease signaling networks and determine whether HCM leads to impaired S1P export and paracrine
function, by enriching and probing the "functional co-translatome" in the RiboTag reporter mice crossed with
HCM mutations. Accomplishing our aims will provide discovery of targets for effective and individualized
therapies for HCM.

## Key facts

- **NIH application ID:** 10812352
- **Project number:** 5R01HL158634-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** PAUL H GOLDSPINK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $782,105
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812352

## Citation

> US National Institutes of Health, RePORTER application 10812352, Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations (5R01HL158634-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10812352. Licensed CC0.

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