This research proposal aims to prevent the phenotypic development of Hypertrophic Cardiomyopathy (HCM) in patients with TRIM63 gene mutations, which lead to sarcomeric protein accumulation within cardiomyocytes. The project is organized around three pivotal objectives: First, we aim to establish a human heart-on-a-chip (HOC) model that faithfully replicates TRIM63-related HCM using patient-derived induced pluripotent stem cells (hiPSCs). This innovative platform will allow for the precise modeling of the disease and the evaluation of therapeutic interventions in a controlled, human-relevant system. Secondly, our project aims to design and synthesize proteolysis-targeting chimeras (PROTACs) that selectively target sarcomeric proteins implicated in TRIM63-associated HCM pathology. This approach represents a significant advancement in drug development, leveraging the ubiquitin-proteasome system to remove disease-causing proteins from affected cells. Lastly, we will rigorously test these PROTACs within the HOC model to assess their ability to reverse or mitigate the disease’s characteristic cardiac hypertrophy and dysfunction.

Collaborative efforts across multiple international laboratories will leverage cutting-edge computational modeling, chemical synthesis, structural analysis, and advanced in vitro tissue models to achieve these goals. This multidisciplinary approach not only aims to develop a novel therapeutic strategy for HCM but also sets the stage for future applications of PROTAC technology and organ-on-chip models in cardiovascular medicine. By addressing the fundamental molecular mechanisms of HCM and pioneering a targeted degradation strategy, this proposal stands to significantly impact the treatment of genetic cardiomyopathies, offering hope for personalized and effective therapies.