# Engineering Cardiac spheroids to study Laminopathies

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $37,732

## Abstract

PROJECT SUMMARY/ABSTRACT
Laminopathies, or LMNA mutations, are hereditary diseases that alter the integrity of the cellular
biomechanics and they are associated with a wide range of diseases including neuromuscular, cardiac,
metabolic disorders and premature aging syndromes. Laminopathies are caused by mutations in the
LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C. Most LMNA mutations
affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. However,
since the lamins stabilize mechanically the nucleus, LMNA mutations alter the integrity of the cellular
biomechanics. It is believed that mutated A-type lamins disrupt the integrity of the cell nuclear
membrane, resulting in nuclear breakage and cell death in tissues exposed to mechanical stress. In
addition, LMNA mutations alter the interaction between the nucleus and the cytoskeleton, “perturbing
cellular force transmission” and preventing nuclear movement of proteins that are needed for healthy
cell function. During the past three years we have investigated the biomechanics of LMNA mutations in
cardiac cells using atomic force microscopy (AFM). LMNA mutations perturb cardiomyocyte gene
expression and biomechanical properties and are the #2 cause of DCMs, leading to heart failure (HF),
arrhythmias, transplantation, and premature death. DCMs are heart muscle diseases that account for
60% of cardiomyopathy cases, are frequently genetic, and are the #1 and #3 causes of heart
transplantation and heart failure. Tragically, DCM strikes young people causing disproportionately high
morbidity (medically, socially, economically, etc.). There exists a clear need for better DCM treatments
for the nearly 1M affected US adults (~1:250). ~50% of cases of DCM are genetic due to >50 DCM
genes, including LMNA. LMNA mutations cause 8% of DCM with a malignant arrhythmia-prone
phenotype, prompting defibrillator implantation (ACC/AHA/HFSA 2017 Guidelines). Since DCM is a
disease characterized by biomechanical impairment of the heart, it is pivotal to understand the cellular
biomechanics and biophysics of this pathology which may bring novel insights that would benefit patient
treatments. In this work we propose to assess how mechanical stresses affect cardiac spheroids
carrying the LMNA mutation. We hypothesis that mechanobiological pathways have the key to find
novel therapeutics for LMNA mutations.

## Key facts

- **NIH application ID:** 11044600
- **Project number:** 3R01HL164634-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Luisa Mestroni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,732
- **Award type:** 3
- **Project period:** 2023-04-05 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11044600

## Citation

> US National Institutes of Health, RePORTER application 11044600, Engineering Cardiac spheroids to study Laminopathies (3R01HL164634-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11044600. Licensed CC0.

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