Research Projects

A comparative exome study on 143 patients with diabetes, 675 HCM patients with diabetes, and a regional control group of 300 Indian individuals without metabolic or cardiovascular diseases has identified sirtuin 2 (SIRT2) point mutations as a possible genetic factor associated with patients of familial hypertrophic cardiomyopathy (HCM). SIRT2 is one of the seven mammalian sirtuin isoforms abundantly expressed in metabolically active tissues, including the heart. SIRT2 regulates various cellular processes, including fatty acid oxidation, gluconeogenesis, insulin sensitivity, lipid synthesis, inflammatory and oxidative stress response processes, autophagy, and mitophagy. Previous studies have demonstrated the cardioprotective role of SIRT2 against pathological hypertrophy. However, the implications of SIRT2 point mutations found in HCM patients remain unexplored. The study proposes to study the impact of SIRT2 point mutations as an underlying genetic factor contributing to the development of HCM in patients carrying these mutations using cardiomyocyte culture model and by generating knock-in mice harboring this specific SIRT2 mutation. The experimental design will employ several state-of-the-art molecular and cell biology techniques and biophysical methods to study the effect of identified point mutations on the structure and function of SIRT2. The research outcome will highlight the role of SIRT2 mutants in familial HCM and the molecular targets that mediate its pathophysiology.