Targeting Immune-Fibroblast Crosstalk in Genetic Dilated Cardiomyopathy

About This Grant

PROJECT SUMMARY Dilated cardiomyopathy (DCM) is one of the most common hereditary heart conditions, yet effective targeted therapies remain lacking. Extensive myocardial fibrosis underscores the critical role of non-myocyte dysfunction, particularly fibroblasts, in disease progression. Concurrently, immune activation and macrophage infiltration are increasingly recognized in DCM, implicating inflammation as a key driver of adverse remodeling. However, the mechanisms by which inflammatory signals activate fibroblasts remain poorly defined. This multi-PI R01 integrates patient-specific induced pluripotent stem cells (iPSCs), 3D cardiac organoids embedded in engineered disease-specific niches, CRISPR-based high-throughput screening, single-cell RNA sequencing (scRNA-seq), bioinformatics, and in vivo DCM mouse models to investigate and therapeutically target this axis. In Aim 1, we will test how inflammatory signals from DCM iPSC-derived cardiomyocytes (iPSC-CMs) initiate tri-cellular crosstalk with macrophages (iPSC-MΦs) and fibroblasts (iPSC-CFs), promoting fibroblast activation through key signaling and feedback loops. In Aim 2, we will evaluate how immune–fibroblast crosstalk contributes to fibrotic remodeling and cardiomyocyte dysfunction using single-cell, monolayer co-culture, and 3D cardiac organoid platforms embedded within engineered fibrotic niches. In Aim 3, we will map immune–fibrotic networks using scRNA-seq and genome-scale CRISPRi/a screens, followed by high-throughput drug screening and validation of prioritized targets, in both iPSC-based systems and in vivo DCM mouse models. Together, this study will define the cellular and molecular mechanisms of immune–fibroblast crosstalk in genetic DCM and accelerate the development of precision antifibrotic therapies.