# The Role of Sarcomeric Protein Alignment in Connexin 43 Localization at Gap Junction

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $67,446

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypertrophic cardiomyopathy (HCM) is a devastating inherited disease that is associated with high incidence of
arrhythmia, conduction anomaly, and sudden cardiac death in the patients. Previous studies have revealed that
heart muscle tissues of HCM patients exhibit disorganized heart muscle cells or cardiomyocytes, randomly
organized sarcomere, and aberrant gap junction structure. Gap junction is a specialized structure that localizes
preferentially at the longitudinal ends of mature cardiomyocytes to facilitate rapid and directional electrical
conduction. In HCM, gap junction is altered and connexin 43 (Cx43), a major gap junction protein in
cardiomyocytes, is randomly distributed along the plasma membrane. While genetic studies have implicated
mutations in sarcomeric proteins such as β-cardiac myosin heavy chain (MYH7) as etiology of HCM, it has been
unclear how the sarcomeric disarray seen in the hearts of patients with MCH can induce disorganized cardiac
gap junctions to result in clinical arrhythmia. I hypothesize that sarcomeric protein alignment plays an important
role in Cx43 localization and alteration of sarcomeric alignment in HCM results in abnormal Cx43 distribution
and increase arrhythmia. The goal of this study is to improve gap junction formation and reduce
arrhythmogenesis in HCM by identifying the key mechanisms that link sarcomeric alignment to Cx43
localization. Specifically, I propose to build upon my expertise in bioengineering to 1) examine effects of
modulating cell shape and cell-cell contact on sarcomeric protein alignment and Cx43 localization in normal
human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and 2) investigate whether the MYH7
mutation-induce sarcomeric disarray and altered Cx43 localization in clinical HCM, can be modeled using MYH7
mutant hiPSC-CMs. The anticipated payoff of the proposed project will be an improved molecular understanding
of arrhythmogenic mechanisms in HCM. These goals are significant because the proposed platform can be
utilized to develop novel anti-arrhythmic therapeutics and further be expanded into other iPSC-CM-based
applications. At the same time, the proposed research training plan will also provide valuable opportunities to
advance my knowledge in stem cell biology and cardiac development, which will complement my existing
expertise in bioengineering and aid my future goal of setting up an independent research group in cardiovascular
medicine.

## Key facts

- **NIH application ID:** 9931265
- **Project number:** 5F32HL142205-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Soah Lee
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931265

## Citation

> US National Institutes of Health, RePORTER application 9931265, The Role of Sarcomeric Protein Alignment in Connexin 43 Localization at Gap Junction (5F32HL142205-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931265. Licensed CC0.

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