# MicroRNA Control of Dilated Cardiomyopathy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $665,737

## Abstract

Dilated cardiomyopathy (DCM)-associated heart failure is a leading cause of mortality worldwide. About a third
of DCM is due to gene variants in a broad range of cardiac muscle proteins. Although this information has
improved patient management, it has not yet led to new therapeutics that target the underlying mechanisms of
disease. A major roadblock is that the consequences of the DCM-causing mutations are not understood in
sufficient detail to identify points of therapeutic intervention. During the first funding cycle of this project, we used
large-scale screening of synthetic microRNAs as an entry point to discover genes that, when inhibited, restored
contractility of induced pluripotent stem cells (hiPSC-CMs) carrying DCM-causing mutations. We identified two
synthetic microRNAs that normalized contractility of DCM cardiomyocytes comparable to CRISPR-correction of
the underlying mutation. Neither microRNA affected isogenic, control hiPSC-CMs, indicating that they act on
disease-related processes. We biochemically identified their targets, identifying 203 genes, of which individual
siRNA-mediated inhibition of 117 restored contractility of TNNT2 mutant DCM mutant hiPSC-CMs from different
patient donors. While some of the candidate genes have been tested as therapeutic targets in heart failure, the
vast majority represent new therapeutic target space for inherited DCM.
This is multi-PI renewal application is to determine the mechanisms of action of these genes and to establish
evidence of disease modifying activity using human genetics and a mouse DCM model. The multi-PI and co-I
team unites expertise in iPSC and animal models, systems biology, and human genetics that will have a
synergistic impact on our long-term goal of defining therapeutic mechanisms for DCM that would not be possible
through separate proposals.
Given the diverse genetics and clinical presentations of inherited DCM, our overarching hypothesis is that
subsets of the candidate genes, and the physiological processes they affect, will revert contractile dysfunction
in a DCM mutation-specific manner. Thus, Aim 1 is to define mechanisms that restore contractile function in
DCM caused by different gene variants, and associate beneficial molecular genetic and metabolic pathways with
particular DCM-causing mutations, Aim 2 is to investigate whether genetic variants linked to each of the miR-
target genes associate with human cardiovascular diseases or quantitative traits using existing GWAS studies,
and Aim 3 is to test whether targets of a microRNA that selectively ameliorates contractility in TNNT2-mutant
hiPSC-CMs converge on ER stress using a mouse knock-in model engineered with the same Tnnt2 mutation as
in the patient hiPSCs.

## Key facts

- **NIH application ID:** 10812167
- **Project number:** 2R01HL130840-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARK MERCOLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,737
- **Award type:** 2
- **Project period:** 2023-12-12 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812167

## Citation

> US National Institutes of Health, RePORTER application 10812167, MicroRNA Control of Dilated Cardiomyopathy (2R01HL130840-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10812167. Licensed CC0.

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