Mechanical and Metabolic Pathways Underlying MYBPC3 Hypertrophic Cardiomyopathy

/ABSTRACT Candidate: Joshua Meisner, MD, PhD is a pediatric cardiologist and physician-scientist focused on understanding the molecular basis of and developing translational therapeutic approaches for pediatric-onset cardiomyopathies. His long-term career objective is to become an independent investigator integrating the biomechanics and metabolism of pediatric-onset cardiomyopathy. Research Context: Truncating variants of myosin-binding protein-C, cardiac type (MYBPC3), are the most common cause of hypertrophic cardiomyopathy (HCM), a leading cause of sudden death and heart failure. The most severe cases of HCM develop substantial hypertrophy during childhood and adolescence. HCM disease progression is proposed to be primarily driven by mechanical and energetic stress from dysregulated myocardial workload. This leads to hypertrophy, fibrosis, and metabolic dysregulation. However, pathophysiology and disease progression in MYBPC3-related HCM remains unclear due to lack of in vivo and in vitro models that replicate human disease. Consequently, the pre-clinical testing of emerging therapeutics is severely limited. To solve this problem, Dr. Meisner developed novel models in both induced pluripotent stem cell cardiomyocytes (iPSC-CMs) and mice that replicate severe, adolescent-onset MYBPC3-related HCM. Specific Aims: Using these two systems, Dr. Meisner aims to elucidate the role of energetic and mechanical stress in MYBCP3-related HCM progression and test for reversibility in early and late stage HCM. In Aim 1, he will establish the time course of hypertrophy, metabolic dysregulation, and fibroblast activation in his MYBPC3- related HCM mouse model. Then, he will test the reversibility of pathology by independent targeting hypercontractility and mitochondrial dysfunction. In Aim 2, using iPSC-derived cardiac tissues under highly controlled biomechanical conditions, he will determine the acute effects of increased mechanical stress and energetic stress on metabolic dysfunction and fibroblast activation with loss of MYBPC3. Career Development Plan: To achieve his long-term career goals, Dr. Meisner has developed a detailed training plan focused on four areas: 1) cardiac metabolism, 2) bioengineering approaches to modulate tensile stress and workload in cardiac tissues, 3) in vivo drug testing and phenotyping, and 4) high-throughput bioinformatics analysis including snRNA-seq approaches to quantify cardiomyocyte- and fibroblast-specific transcriptional changes during disease progression. A five-year plan encompassing selected coursework and project-based mentoring will equip Dr. Meisner with a unique skill set applicable to the study of a broad range of pediatric onset cardiomyopathies. His career development and transition to independence will be supported by close mentorship from an interdisciplinary team with expertise in each scientific training objective. Environment: The University of Michigan offers the ideal environment for Dr. Meisner to pursue this training, with the outstanding guidance of well-established mentors dedicated to his success. Project Number: 1K08HL179262-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Joshua Meisner | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $167,400 | Activity Code: K08 | Study Section: NHLBI Mentored Clinical and Basic Science Study Section[MCBS (JA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08HL17926201