Reverse electron transport inhibition to suppress fibroblast activation in aging

Project Summary/Abstract This project explores the critical and underappreciated role of reverse electron transport (RET) in lung aging and idiopathic pulmonary fibrosis (IPF), a complex biological phenomenon marked by a progressive decline in lung function and increased susceptibility to chronic diseases. IPF, in particular, presents a relentless clinical challenge with limited therapeutic options and a median survival of only 2-5 years post-diagnosis. Emerging evidence implicates mitochondrial dysfunction, especially RET, in the advancement of this condition. RET, characterized by an atypical backward flow of electrons through the mitochondrial electron transport chain, leads to a surge in reactive oxygen species (ROS) production and NAD+/NADH ratio imbalance. This dysfunction is believed to be exacerbated by aging-related mitochondrial DNA damage, heightening oxidative stress and metabolic disturbances associated with IPF pathogenesis. Our investigation, supported by promising preliminary data utilizing the RET inhibitor CPT-2008, aims to elucidate RET's impact on pro-fibrotic gene expression in lung fibroblasts and its role in lung collagen accumulation and fibrosis. The first objective is a detailed gene expression analysis to understand the specific influence of RET lung fibroblasts, considering variables like aging and lung injury. The second objective assesses the therapeutic potential of RET inhibition in ameliorating lung fibrosis, employing both young and aged mouse models. This part of the study extends to evaluating RET inhibition's effects on human IPF lung tissue, thereby linking animal model findings to potential clinical applications. This research is poised to significantly enhance our understanding of the mechanisms underlying lung aging and IPF. By shedding light on the previously unexplored role of RET in these processes, the project aims to unveil novel pathways and therapeutic targets, offering foundational advancement in knowledge about the role of RET and a transformative perspective in the management and treatment of IPF, a condition of major concern in the aging population.