# Thrombospondin 4 regulates adaptive ER stress responseRenewal - Resubmission - 1

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $605,807

## Abstract

Abstract
Similar to skeletal muscle myofibers, cardiomyocytes in the heart appear to be particularly susceptible to
membrane instability and rupture during disease, in part because of their contractile status that produces
ongoing mechanical deformation. Mutations in genes that disrupt or weaken the membrane anchoring
proteins of the dystrophin-glycoprotein complex (DGC) or the integrin adhesion network causes a wide range
of muscular dystrophies that also cause cardiomyopathy. We have shown that the thrombospondin gene
family (Thbs1-5) plays a critical role in membrane stability through both effects on the ER stress response
and secretory pathways, as well as controlling the integrin complexes present on the sarcolemma. In our
previous cycle of funding, we showed that overexpression of Thbs3 has a remarkable effect of reducing
sarcolemma stability in heart (opposite of Thbs4) by removing large arrays of integrin heterodimers from the
adhesion complexes, while Thbs3 KO mice have enhanced integrin membrane levels and are protected
from insults that would otherwise cause cardiomyopathy, like overexpression of Thbs4 that also increases
membrane stability by increasing membrane attachment protein complexes in the sarcolemma. However,
several critical mechanistic questions remain to be addressed in attempting to translate our findings into
therapeutic approaches. Here we propose the unifying hypothesis that the cardiac expressed Thbs proteins
primarily function from within the secretory pathway in mediating the stability, or recycling of membrane
attachment complexes, which has profound effects on sarcolemmal stability and healing dynamics within the
heart with both acute injury and chronic disease, which will suggest potential novel gene therapeutic
ventures for cardiomyopathy in heart failure or with muscular dystrophy. To interrogate this hypothesis, we
propose the following 2 Specific Aims: 1) Mechanistically define how Thbs3 and Thbs4 antithetically regulate
sarcolemmal stability through integrin processing for gene therapy application in cardiomyopathy and
muscular dystrophy. 2) Examine the molecular mechanism of dilated cardiomyopathy in a mouse model for
the Human THBS4 D717N variant. The goal will be to better understand human heart disease through the
Thbs gene family and how it regulates membrane stability and adhesion complex activity. Translational
implications are that a better understanding of these molecular mechanisms will suggest why humans with
mutations in Thbs4 show dilated cardiomyopathy and will suggest modified versions of Thbs4 to be used in
gene therapy approaches to treat muscular dystrophy, as well as a wide array of heart diseases in which the
membrane is weaker.

## Key facts

- **NIH application ID:** 10792699
- **Project number:** 2R01HL105924-13A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jeffery D Molkentin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,807
- **Award type:** 2
- **Project period:** 2011-01-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792699

## Citation

> US National Institutes of Health, RePORTER application 10792699, Thrombospondin 4 regulates adaptive ER stress responseRenewal - Resubmission - 1 (2R01HL105924-13A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10792699. Licensed CC0.

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