# Thrombospondin 4 Regulates Adaptive ER Stress Response

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $450,762

## Abstract

Abstract
Similar to skeletal muscle myofibers, cardiomyocytes in the heart appear to be particularly
susceptible to membrane instability and rupture with the slightest perturbation, 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 recently shown that the thromobospondin 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 select Thbs proteins in the heart
or skeletal muscle can have remarkable effects on sarcolemma stability in heart and skeletal
muscle cells, while KO mice for the same Thbs genes have reciprocal effects that complement
exactly the overexpression effect. Thus, in this renewal application we will attempt to uncover the
molecular mechanisms whereby the Thbs proteins serve to regulate sarcolemmal stability during
ER stress and healing, in part, through coding for select integrin heterodimers on the cell surface
of cardiomyocytes. We propose the unifying hypothesis that the Thbs proteins are stress-induced
ER resident factors that facilitate healing after injury or with stress by serving as intra-vesicular
chaperones for sarcolemmal delivery of integrins through the secretory pathway. To address this
hypothesis we propose 3 specific aims. Aim #1 will compare Thbs3 versus Thbs4 in regulating
cardiac sarcolemma stability and disease with doxorubicin induced cardiomyopathy and muscular
dystrophy (models of membrane instability). Aim #2 we will attempt to rescue the enhanced
cardiac disease phenotype and sarcolemmal instability of Thbs3 TG and Thbs4-/- mice by integrin
overexpression in vivo. Aim #3 we will examine the molecular mechanisms whereby Thbs3
reduces membrane stability and Thbs4 increases it through integrin processing within the cell.
Defining the molecular mechanisms in play and how selective integrin sorting is achieved by the
Thbs proteins during stress stimulation and healing will suggest novel treatment approaches for
MI injury and post-ischemic heart failure.

## Key facts

- **NIH application ID:** 9861253
- **Project number:** 5R01HL105924-10
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jeffery D Molkentin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,762
- **Award type:** 5
- **Project period:** 2011-01-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861253

## Citation

> US National Institutes of Health, RePORTER application 9861253, Thrombospondin 4 Regulates Adaptive ER Stress Response (5R01HL105924-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861253. Licensed CC0.

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