# DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $531,704

## Abstract

PROJECT SUMMARY
Goal: We propose to utilize a series of novel human iPSC-based cardiac microphysiological systems of
increasing complexity to investigate the hypothesis that maturation of dystrophic cardiomyocytes is necessary
to elucidate correct disease phenotype development in vitro. The aim is to create a multifaceted screening
system using several core technologies developed by our group to evaluate different aspects of myocardial
electromechanical function. We have developed the ability to engineer pluripotent stem cells from patient urine,
enabling non-invasive cell sampling from human subjects. Furthermore, we have collected preliminary data
demonstrating that application of combinatorial maturation stimuli to healthy and dystrophin-null
cardiomyocytes helps stratify the disease phenotype. Based on these achievements, we posit that the use of a
targeted set of functional assays in combination with appropriate maturation stimuli will provide a more
comprehensive understanding of disease progression in muscular dystrophy. Focus/Aim: Our proposed
research focuses on the use of techniques with the potential to act synergistically to enhance cardiac
phenotype development in stem cell-derived cardiomyocytes through manipulation of different cellular
mechanisms. Specifically, we will investigate the effect of structural organization by nanopatterned substrates,
nuclear receptor signaling by thyroid hormone, and alterations in metabolic signaling pathways by Let-7
microRNA over-expression on the development of healthy cardiomyocytes and their dystrophin-null
counterparts created using CRISPR-Cas9 gene editing technology. Nanotopographic microelectrode arrays
will be used to evaluate electrophysiological function (Aim 1), while nanopatterned cell sheet stacking
technology will be used to create 3D cardiac patches for analyzing contractile function (Aim 2) as well as
organized 3D ventricle structures for assessing pressure generation and stroke volume (Aim 3). Each of these
systems will be used to evaluate a panel of drugs for their potential to ameliorate the dystrophic phenotype.
The compounds chosen for this study target a range of metabolic, structural, and signaling pathways known to
be associated with different aspects of muscular dystrophy pathology. The analysis of multiple functional
endpoints for each compound will therefore provide more comprehensive information on the likely effect of
drugs when administered to human patients. The movement from platforms with higher levels of throughput to
those with higher degrees of biomimicry, as the work transitions from Aim 1 to Aim 3, constitutes a natural
“funneling” of the drug screening process. Candidates identified using simpler multiplexed models will be re-
evaluated using systems that offer closer representations of the native tissue, and provide physiological
endpoints analogous to those monitored in patients. As such, the proposed method for studying maturation
and dystrophic phenotype d...

## Key facts

- **NIH application ID:** 10164856
- **Project number:** 5R01HL146436-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Deok-Ho Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $531,704
- **Award type:** 5
- **Project period:** 2020-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164856

## Citation

> US National Institutes of Health, RePORTER application 10164856, DISEASE MODELING AND PHENOTYPIC DRUG SCREENING FOR DYSTROPHIC CARDIOMYOPATHY (5R01HL146436-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164856. Licensed CC0.

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