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.

Grant Number: 1R21AG093042-01
NIH Institute/Center: NIH
Principal Investigator: Mallar Bhattacharya