# Patient Specific Induced Pluripotent Stem Cell Derived Cardiomyocytes to Define Mechanisms of Electrical-Mechanical Dysfunction in DilatedCardiomyopathy

> **NIH NIH K08** · STANFORD UNIVERSITY · 2020 · $168,156

## Abstract

This proposal describes a five-year mentored physician-scientist training program for the candidate to develop
his proficiency in the scientific method, mentorship, writing and grantsmanship. Furthermore, the candidate will
acquire independent skills in areas of genome editing, genotype-phenotype analysis and cardiac calcium
signaling. This will be accomplished in the context of investigating the role of late sodium current in dilated
cardiomyopathy. Late sodium current arises from dysfunctional human gated voltage channels and is known to
contribute to other cardiac disorders, but the role of late sodium current in dilated cardiomyopathy remains
incompletely understood and largely based on animal models. The hypothesis examined here is that enhanced
late sodium current results in mechanical and electrical dysfunction in dilated cardiomyopathy by further
aggravation of calcium handling and gives rise to delayed after depolarizations. This proposal aims to examine
the cellular mechanism of disease of the late sodium current using human induced pluripotent stem cell derived
cardiomyocytes (iPSC-CM). All iPSC-CMs in this proposal will be matured using a novel protocol that augments
electrical, mechanical and cell signaling properties of iPSC-CMs closer to properties of adult cardiomyocytes.
First, cardiomyocytes from three dilated cardiomyopathy patients with SCN5A variants will be examined to
determine if the late sodium current is the driving mechanism of cardiomyopathy in those cases. Subsequently,
similar experiments will be repeated in iPSC-CMs from patients with dilated cardiomyopathy not caused by
variants affecting sodium channel loci. Late sodium channel current will be blocked and enhanced to evaluate
the impact on mechanical and electrical phenotype. Lastly, the role of the ryanodine receptor in mediating
delayed after depolarizations will be tested to determine if this cellular mechanism is the pathway by which the
late sodium current contributes to arrhythmia. This will uncover genotype-specific disease mechanisms related
to late sodium current that may explain heterogeneity in electrical and mechanical dysfunction across cases of
dilated cardiomyopathy and identify novel therapeutic targets. This proposal takes a novel approach of using
iPSC-CM derived from patients with multiple causative variants of DCM to study differences in disease
mechanism. Results of these experiments will provide preliminary data and expertise to future work examining
role of other genetic variants in influencing electrical and mechanical dysfunction in DCM and identifying
genotype-specific therapies for patients with cardiomyopathy. These investigations will be performed under the
guidance of the candidate’s advisory committee, which possesses significant expertise in the skills applied in
this proposal. The environment at Stanford is ideal for this research proposal and provides a rich setting for the
candidate’s growth as an independent investigator. At the...

## Key facts

- **NIH application ID:** 9987701
- **Project number:** 5K08HL135343-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Karim Sallam
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,156
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987701

## Citation

> US National Institutes of Health, RePORTER application 9987701, Patient Specific Induced Pluripotent Stem Cell Derived Cardiomyocytes to Define Mechanisms of Electrical-Mechanical Dysfunction in DilatedCardiomyopathy (5K08HL135343-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9987701. Licensed CC0.

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