Friday, May 9, 2025
5/9/2025
From genetic basis to mechanisms for Heart Failure - SUMMARY Heart failure (HF) is a global epidemic affecting millions of people worldwide. Despite improved medications and device therapies for the management of HF in clinical practice, the morbidity and mortality of HF remain strikingly high. In the United States, HF prevalence is projected to increase by over 40% till 2030. There is an urgent need to identify novel HF therapies that are more effective and targeted. There are many known risk factors for HF including age, HTN, cardiovascular disease (CVD), diabetes, and genetics. Genome-wide association studies (GWAS) have started to identify common genetic risk loci associated with HF. In the largest HF GWAS to date completed in 2022, 47 loci were identified. This number is anticipated to increase quickly in the upcoming years. While genetic discoveries hold promise to discover new targets for therapeutic development, a major challenge with GWAS for HF is identifying the causative genes and in turn the underlying mechanisms through which these genes modulate the risk for HF. There is a critical unmet need to accelerate functional interpretation of genes associated with HF in disease-relevant cell type to identify genes or pathways that are causal for HF. To address this challenge, we have applied two complementary, high throughput assays, Cell Painting and Perturb-seq to link genes associated with HF to discrete molecular and cellular phenotypes. To accomplish this goal, we developed and optimized CARDIO (Cardiomyocyte Analysis using Robust Cell Painting Imaging and Output), an assay that allows high-content morphological profiling of human pluripotent stem cell derived CMs (hPSC- CMs). We applied our CARDIO approach to a CRISPR knockout assay of 37 genes selected from a GWAS of cardiac contractile function. We identified a novel role for two genes, YWHAE and HSPB7 with divergent effects in CM morphology and function. Functional validation using engineered heart tissues (EHTs) demonstrated YWHAE knockout (KO) had a similar functional profile as titin KO. In contrast, loss of HSPB7 induced a hypertrophic phenotype and restored contractile function in a titin model of DCM. our approach demonstrates that the combination of morphological profiling with functional assessment can identify novel genes involved in heart failure at scale, and potentially identify biological mechanisms for therapeutic development. In this proposal, we will leverage our novel functional genomic approach to investigate the roles of all GWAS genes associated HF. We will analyze the impact of loss of the genes at the GWAS loci for HF using a combination of CARDIO or imaging based morphological profiling (Aim 1) and Perturb-seq or transcriptional profiling (Aim 2). Finally, we will seek to validate leading candidates in engineered heart tissues (Aim 3). These studies enable us to ascertain relationships between HF risk genes and cellular phenotypes at scale, providing a framework for rapid validation of genetic discoveries to disease mechanisms, which will generate testable hypotheses for future investigations using animal models or human cardiac organoids.
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