Research Projects

Background: Lung fibrosis (LF) is a major contributor of lung pathology-associated global mortality and morbidity. IPF is the most complicated phenotype with complex pathogenesis, characterized by progressive damage to the lung parenchyma and interstitium. Average lifespan of patients is 2-5 years. Dearth of effective therapeutic modalities severely cripples the management efforts. FDA-approved antifibrotic drugs, pirfenidone and nintedanib, fairly retard LF. However absolute prevention or complete resolution is unachievable, thereby warranting identification of effective actionable targets to be exploited for novel anti-fibrotic drug discovery. This project is an extension of the recently completed DST-SERB-funded project ECR/2017/002573 where we successfully demonstrated mitochondrial sirtuin, SIRT3 as a major regulator of pulmonary myofibroblast (myoFB) transdifferentiation by controlling nuclear sirtuin SIRT6 and aberrant mitophagy-macroautophagy uncoupling. However, it is yet elusive how exactly SIRT3 prevents SIRT6 downregulation by TGF-β1 in myoFBs to mediate dynamic nucleus-mitochondria crosstalk during fibrosis. Being a pivotal factor resisting myriad fibrogenic pathways, mitochondrial deacetylase SIRT3 controls TGF-β1-induced mitochondrial oxidative stress which crucially contributes to myoFB transdifferentiation involving deregulation of mitochondrial dynamics and mitophagy. But precise molecular player/s connecting SIRT3 and aberrant mitochondrial metabolism is yet unknown but can serve as promising actionable target. Hypothesis and objective: We hypothesize that the mitochondria-located reactive oxygen species modulator 1 (ROMO1) can be the putative connector whose upregulated expression (preliminary data) results in mitochondrial stress. We propose a role of ROMO1 in maintaining hyperfused mitochondria, in the apoptosis-resistant myoFBs, by stabilizing OPA-1 while increasing ROS to trigger SIRT6 degradation and ensure the persistence of activated myoFBs for overwhelming ECM deposition and display of senescence-associated secretory phenotype. Brief Work plan: Physical interaction between SIRT3-ROMO1 and SIRT6-ROMO1 will be primarily checked. Putative lysine deacetylation sites on ROMO1 will be explored. Plausible regulatory role of ROMO1 on myoFB aberrant mitochondrial dynamics, mitophagy-autophagy crosstalk, apoptosis and senescence will be examined. High resolution confocal microscopy, ChIP, EMSA, mitochondrial metabolic assays, in vitro acetylation, qRT-PCR, and immunoblotting will be done. Significance: The study carries immense translational relevance as it aims to identify mitochondria-based actionable targets in LF which can be exploited for novel non-invasive anti-fibrotic drug discovery. Precisely, ROMO1 may prove to be a possible therapeutic candidate in treating LF along with SIRT3 and SIRT6. Overlapping molecular events in LF and lung cancer will further ensure the utilization of this knowledge in anticancer research.