# Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $392,682

## Abstract

Project Summary
Dilated cardiomyopathy (DCM) is a leading cause of heart failure. Genetic DCM, which runs in families, is now
more commonly diagnosed, accounting for up to half of the reported cases. Despite the progress in unraveling
the genetic basis of DCM, there is still a large gap in our understanding of the molecular events and signaling
pathways that lead from a mutation to diverse disease phenotypes. The recent advent of new technologies,
such as patient-specific induced pluripotent stem cells (iPSCs) and genome editing (CRISPR/Cas9), provide
an unprecedented opportunity to study associations between genetic variability and disease susceptibility. By
combining these breakthrough technologies, we are now poised to address one of the most critical issues in
familial DCM, namely, the genotype-phenotype relationship from the ever-growing number of DCM-associated
gene mutations. The overarching goal of our proposal is to utilize a multidisciplinary approach that integrates
patient-specific iPSCs, genome editing, genetic screens, next generation sequencing technologies and
transgenic animal models to gain novel insights into genotype-phenotype associations, and to dissect the
molecular mechanism of genetic DCM pathogenesis. Our preliminary studies have implicated the activation of
the unfolded protein response (UPR) in the endoplasmic reticulum (ER) in the pathogenesis of DCM in a model
of patient-specific iPSC-CMs. The central hypothesis of the revised proposal is that certain DCM mutations
alter Ca2+ homeostasis and cause chronic ER stress, leading to prolonged activation of the UPR signaling. We
will pursue three specific aims. In aim 1: we will establish an experimental platform to study the genotype-
phenotype association of cardiac troponin T (TNNT2) and phospholamban (PLN) gene variants associated
with DCM; in aim 2: we will decipher the role of ER stress and UPR activation in genetic DCM; and in aim 3:
interrogate the mechanisms of DCM pathogenesis associated with TNNT2 mutations in vivo. We have
assembled a multi-disciplinary team with extensive complementary and integrated expertise. We have
provided compelling preliminary data to support the soundness of our hypothesis-driven research proposal,
and we are well positioned to achieve the project goals within five years. If successful, our studies will provide
a new paradigm for understanding the pathogenesis and treatment of familial DCM.

## Key facts

- **NIH application ID:** 9949435
- **Project number:** 5R01HL139679-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ioannis Karakikes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,682
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949435

## Citation

> US National Institutes of Health, RePORTER application 9949435, Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine (5R01HL139679-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949435. Licensed CC0.

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