# Human iPSCs for Elucidating Intercellular Crosstalk Signaling in Dilated Cardiomyopathy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $696,854

## Abstract

PROJECT SUMMARY
LMNA-related dilated cardiomyopathy (DCM) is among the most prevalent forms of inherited heart disease,
characterized by severe systolic dysfunction and ventricular chamber enlargement. Major hallmarks of
LMNADCM also involve features of non-myocyte dysfunction including myocardial fibrosis and endotheliopathy.
However, precise mechanisms of intercellular communication in the heart remain unclear, in part because the
human cardiac secretome to date has been poorly defined. To overcome this challenge, we propose to leverage
human iPSCs, genome-editing technology, and state-of-the-art omics methods to identify and investigate
crosstalk signaling pathways potentially involved in LMNA-DCM pathogenesis. In Aim 1, we will comprehensively
profile the baseline secretomes of each cell type by employing high-throughput aptamer-based proteomics
methods, and perform trans-well co-culture assays to systematically evaluate the downstream functional
consequences of cellular crosstalk. In Aim 2, we will complement these studies with further investigation into
intercellular communication mechanisms in engineered heart tissues (EHTs) of varying LMNA-DCM / control cell
type compositions. The EHTs will be subsequently analyzed by single-cell RNA sequencing (scRNA-seq) to
predict cell-cell crosstalk modalities and construct a list of unique and shared ligand receptor pairs across
conditions. In Aim 3, we will perform large-scale high-throughput screening of >4,000 compounds using
multicellular iPSC-derived cardiac organoid (iPSC-CO) differentiated from tri-lineage reporter lines. Selected
candidates will be validated and further investigated using proteomics and targeted gain/loss-of function studies.
We anticipate that the successful completion of these studies will lead to new mechanistic insight into DCM
pathogenesis, and help develop novel therapeutic strategies that can impede and reverse aberrant crosstalk
signaling between cardiac cell types in the diseased heart.

## Key facts

- **NIH application ID:** 10444652
- **Project number:** 2R01HL141371-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lei Stanley Qi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $696,854
- **Award type:** 2
- **Project period:** 2018-05-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444652

## Citation

> US National Institutes of Health, RePORTER application 10444652, Human iPSCs for Elucidating Intercellular Crosstalk Signaling in Dilated Cardiomyopathy (2R01HL141371-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10444652. Licensed CC0.

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