Mitochondrial Dysfunction and Molecular Therapy in Pulmonary Oxygen Toxicity (21-000000696)
Abstract
Two organ systems the pulmonary system and the central nervous system (CNS) are highly susceptible to hyperbaric oxygen toxicity,. There is great desire in the diving community for development of mitigation strategies to prevent hyperbaric oxygen toxicity and p,rotect personnel in undersea medicine applications. Oxygen toxicity, which can be deadly, causes cellular dysfunction rooted in dera,ngements of mitochondrial processes. Decrements in mitochondrial function resulting from hyperoxic exposure promote a cascade of lun,g cellular dysfunction, which integrates into severe organ dysfunction (e.g., pulmonary insufficiency) leading potentially to death., A similar cascade in the CNS is manifest by seizures and other symptoms. While many lung and CNS physiological effects of oxygen to,xicity are known, the organelle- and molecular-level basis of these impairments are not well understood. Identification of the speci,fic molecular and mitochondrial deficits occurring in lung cells in response to hyperbaric oxygen exposure enables therapeutic insig,hts and facilitates the development of cytoprotective interventions to reduce pulmonary injury resulting from such stressors. It als,o enables knowledge to be cross-applied to CNS applications, for which similar cell-based studies are unrealistic.We hypothesize tha,t hyperbaric oxygen elicits organelle and biochemical signatures mark onset and severity of oxygen toxicity in pulmonary cells. We f,urther hypothesize that cytoprotective interventions will mitigate these responses. We will test our hypotheses using relevant pulmo,nary cell lines and putative therapeutics in three Specific Aims designed to: 1) quantify mitochondrial and cellular baselines with/,without putative therapeutics; 2) quantify mitochondrial and cellular responses to hyperoxic exposures; and 3) determine effects of,putative therapeutics to mitigate hyperoxic responses in cells. Measures will include mitochondrial dynamics and bioenergetics as we,ll as relevant cellbiochemical markers of oxygen toxicity. Putative therapeutics will include Mito-Q, caffeine and -aminobutyric ac,id.This research will address two key issues of high relevance to Navy via ONRs explicit Undersea Medicine & Performance Research C,oncentration Areas: 1) mitigation of hyperbaric oxygen toxicity; and 2) diver performance optimization. Understanding the molecular,mechanisms of pulmonary cell dysfunction, including mitochondrial failure, resulting from hyperbaric oxygen is critical to identifyi,ng and testing potential mitigation strategies relevant to both lung and CNS. This work further enables the direct two-way exchange,of information between multiple labs regarding discovery of underlying mechanisms of oxygen toxicity in cells, tissues and organs an,d from basic to translational realms in advancing oxygen toxicity research. Our proposed basic science experiments bridge scientific,ally and programmatically to in vivo translational-based studies (e.g., Gasier lab at Duke University) in which both CNS and pulmona,ry oxygen toxicity are studied, and to CNS tissue-based studies (e.g., Dean lab, University of South Florida).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2022
- Source ID
- N000142212170
Entities
People
- David M Eckmann
Organizations
- Office of Naval Research
- Ohio State University
- United States Navy