Research Projects

Rationale: Cardiovascular diseases (CVDs) are the leading cause of death worldwide (Organization 2016). In India, a quarter of all cases of mortality are attributed to CVDs (Prabhakaran, Jeemon et al. 2016). A significant subset of these deaths are attributed to cardio-metabolic diseases (de Waard, Hollander et al. 2018). Metabolic disorders such as obesity, insulin resistance, and diabetes are characterised with dyslipidemia, which quickly progresses to myocardial lipotoxicity and predisposes patients to heart failure. These syndromes pose an enormous personal, social and economic impact; and are likely to adversely affect India's economic growth in the coming years. The current therapeutic options against heart failure treat the symptoms and not the undelying cause. Incomplete understanding of the molecular players involved in the development and progression of heart failure severly limits the development of novel therapeutics. Our preliminary data demonstrates a significant increase in PARP16 protein levels in the hearts of high fat diet-fed mice as well as db/db mice. These mice are robust models for the study of lipid metabolism disorders, and suffer from myocardial lipotoxicity. Consistent with this, we observed significant reduction in fatty acid uptake and lipid accumulation upon PARP16 knock-down in vitro in neonatal rat cardiomyocytes. Based on these results, we hypothesize that PARP16 may serve as a critical regulator of cardiac lipotoxicity. Myocardial lipotoxicity may develop via perturbations in FA uptake, FA oxidation and lipid storage. Therefore, in the proposed study, we aim to identify the role of PARP16 as a regulator of these pathways; and investigate the molecular mechanisms by which PARP16 may be implicated in the development of cardiac lipotoxicity. Hypothesis: Based on our preliminary findings, we hypothesise that PARP16 may regulate key proteins involved in the development and progression of cardiac lipotoxicity. Models employed in the study: In the proposed study we will generate whole body PARP16 knock-out and cardiomyocyte specific PARP16 transgenic mice to study the relevance of PARP16 in lipid metabolism. We will characterise the metabolic perturbations in the PARP16 whole-body knock models and cardiac specific PARP16 transgenic mice. Primary neonatal cardiomyocytes from rats will serve as the in vitro study system to test and validate our hypothesis. Significance: We believe that the findings of proposed project will provide novel insights into molecular players involved in cardiac lipotoxicity. We expect to identify the regulation of key proteins that mediate cardiac metabolism. The molecular players identified could serve as a potential therapeutic target in treating patients with metabolic comorbidities associated with heart failure.