Research Projects

Hypertrophic cardiomyopathy (HCM) is a predominantly monogenic cardiac muscle thickening disorder that leads to abnormal diastolic function and eventually causes heart failure. Pathogenic variants in sarcomere apparatus genes are the leading cause of this disorder. However, for around 50 to 60% of HCM cases, the exact causative genes were not known yet. In our HCM gene discovery study using the South Indian cohort (n=300), we have identified pathogenic variants in a new gene named tubulin tyrosine ligase (TTL). The enzyme TTL controls the tyrosination/ detyrosination cycle of microtubules, a post-translational modification that dictates its function in cardiomyocytes. Thus, we hypothesize that the TLL variants may modulate their enzymatic activity and cause HCM by impeding the tyrosination cycle and affecting microtubule organization, dynamics and stability. In this proposal, through the following aims, we will understand the functional significance of TTL in causing HCM: 1. Characterizing a representative TTL variant-specific iPSC-derived cardiac organoid for hypertrophy phenotypes, 2. In vitro tyrosination assay to find out whether the representative TTL variant modulates its enzymatic activity, 3. Understand whether the representative TTL variant influences the microtubule’s organization, dynamics and stability and 4. Previous literature and our preliminary results support redox involvement in TTL gene induced cardiomyopathy pathogenesis. Hence, we will delineate detailed cellular redox and antioxidant mechanisms in TTL variant induced organoids. Identifying TTL variant-specific molecular mechanisms linked with cardiomyopathy pathogenesis will aid in developing precision medicine strategies for treating this disorder.