Characterizing determinants of cellular senescence and epigenetic dysregulation on tobacco smoke exposure in lung

About This Grant

Project Summary/Abstract Cigarette smoking is the main cause of occurrence of Chronic Obstructive Pulmonary disease (COPD). Studies show that cigarette smoke (CS)-mediated increase in cellular senescence causes premature ageing in the lung, thereby leading to the development of COPD. However, the exact mechanism of disease development via alterations in cellular senescence over a prolonged period in CS-induced COPD is not known. In this respect, various inter-individual variations are observed amongst regular smokers, thus indicating potential involvement of epigenetic regulations in modulating the downstream signaling. Considering this I hypothesize that the epigenetic regulation of cellular phenotypes and gene expression of cellular senescence- associated genes (p16, p21 and p53) drives disease-fate towards emphysema upon chronic CS exposure. To test this hypothesis, I propose to: (1) determine the time (1, 3, and 6 months(mo)) and age-dependent (2mo versus 18 mo) effects of CS-exposure on the lung cellular senescence and associated epigenetic regulation in vivo using SNARE-sequencing (K99 phase), and (2) study the determinants of cellular senescence and associated epigenetic mediators in primary human small airway epithelial cells (SAECs) from healthy and diseased (COPD) individuals (R00 phase). My postdoctoral work has shown that clearance of senescent cells results in reduction of CS-induced neutrophilic inflammation and reversal of alveolar wall damage in mouse model (p16-3MR). Thus, studying the CS-induced changes in the lung neutrophil and epithelial cell population is the focus of this project. Upon completion of these aims, I will be able to identify gene targets and associated chromatin sites that are altered on cigarette smoking and associate them with disease development in COPD. Use of two mouse models (C57BL/6J and p16-3MR) will help in understanding the role of p16-dependent senescence in CS-mediated alterations in the lung. Additionally, use of Multiome (SNARE-seq) technology in Aim1 will provide a chance to identify unique cell phenotypes based on differentially expressed genes and correlate them to the epigenetic signatures within the cell upon CS exposure. These results would lead to future publications, collaborations, and grant proposals, thus helping to launch my career as an independent researcher in the field of lung biology.