Group Leader Murdoch Childrens Research Institute Melbourne, Victoria, United States
Abstract: Cardiomyopathies are diseases of the heart muscle. The key to developing therapies that directly target the cause of cardiomyopathies is understanding the molecular mechanisms underlying pathology. To do this we have taken a broad approach profiling clinical samples, mouse models and iPSC derived cardiac cells by both proteomics and transcriptomics. Firstly, we performed a large-scale analysis of single nuclei RNA-seq data sets from patients with dilated cardiomyopathy (DCM), combining publicly available datasets with our paediatric samples. Our findings suggest that defined fetal gene re-activation in DCM is not restricted solely to CMs but is broadly re-engaged in non-CM populations, including cardiac fibroblasts. We have evaluated these gene networks in hiPSC-derived cardiac cells, encompassing various genetic forms of DCM. Through this evaluation, we identify a conserved set of fetal genes that may represent the core functional gene network driving DCM. These core genes could provide critical insights into the underlying molecular mechanisms driving DCM from the earliest stages of cardiogenesis and potentially serve as targets for therapeutic interventions. In parallel, we have used proteomics to profile hypertrophic cardiomyopathy (HCM). Misfolded and aggregated sarcomeric proteins in heart muscle cells disrupt cellular functions and contribute to HCM disease progression. Therefore, protein quality control mechanisms, such as the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway, play a crucial role in maintaining sarcomere homeostasis and contraction in cardiac muscle cells. Our clinical and in vitro studies identified a signalling nexus at the M-Band of the sarcomere, containing a number of E3 ubiquitin ligases. Deletion of one of these E3 ubiquitin ligases, TRIM55, compromises contraction demonstrating the UPS is necessary for normal contraction. Mass spectrometry and RNA sequencing analysis revealed sarcomere organisation and muscle contraction was altered in TRIM55 deficient cardiomyocytes. Thus, we have identified a diverse array of molecular networks underlying cardiomyopathies.
Funding Source: Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW (Grant number NNF21CC0073729)
