Defining New Mechanisms to Uncover the Early Developmental Manifestations of Arrhythmogenic Cardiomyopathy in Children

Lay Summary:  We believe our proposal has ground-breaking potential since it presents biological importance towards an entirely new field in genomics/bioinformatics and ncRNA biology much as miRNA had an impact in the ncRNA biology field (including new tools to study this biology). We also believe our proposal will set the stage towards identifying right heart specific markers that have remained elusive in the field, while uncovering novel biological causes and mechanisms underlying the early developmental manifestation of AC and sudden cardiac death in children that also bring to light a new entry point to study and intervene with the developmental causes of AC at the therapeutic level. This knowledge can also be exploited in regenerative medicine to instruct stem cells towards precisely generating cardiac cells of a compartmentalized nature (right versus left), which can be used to study right heart developmental pathways while also refining tissue engineering approaches as well as directed stem cell therapies for compartmentalized heart diseases, such as AC, that are playing an increasingly prevalent role in pediatric populations.

Arrhythmogenic Cardiomyopathy (AC) is a devastating genetic-based cardiomyopathy that classically affects the right heart and leads to sudden cardiac death in young children and adults, including young athletes. However, the early developmental cues governing why the right heart specifically becomes diseased in children with AC remains unclear. Through preliminary studies in a pediatric-based mouse model of AC that our laboratory generated, we uncovered a series of novel yet not understood molecular regulators of gene expression called short non-coding (nc)-RNAs that were uniquely dysregulated in the right heart of this mouse model of AC, which could be major participants in the right heart disease observed in AC in children. Our working hypothesis was that these short ncRNAs are molecular signatures that specify the right heart and their perturbation may trigger the right heart disease underlying AC in children. Funds from the Saving tiny Heart Society allowed our laboratory to use genomic and transcriptomic methods to identify and validate the unique molecular signature that defines the right heart during development and the key players perturbed in the right heart of our pediatric-based mouse model of AC. We were also able to generate unique molecular tools to genetically perturb the balance of these short ncRNAs in a human cardiac model system to determine its early developmental role in human AC. Using this unique human cardiac model system, we are now assessing the effects of the imbalance of these short ncRNAs on cellular disease features associated with AC. We believe the results of our proposal can impact survival of children with AC as they identify early molecular pathways that are unique to the right heart, which can then be manipulated to tailor therapies to improve right heart function in children with AC. Exciting new stem cell based therapies are also being exploited for heart diseases but are primarily directed to left heart diseases, thus, our proposal provides an avenue in which to instruct stem cells to generate right heart cells, which can help refine and direct stem cell therapies for the right heart disease observed in children with AC.