Connecting Lipid Oxidation To Cellular Dysfunction In Hyperbaric Oxygen Toxicity
Abstract
Oxygen toxicity, leading to acute pulmonary and central nervous system damage, is an ongoing risk to Navy divers using high-oxygen gas mixes. While current diving protocols have minimized the incidence of hyperbaric oxygen toxicity events, the physiological origins of oxygen toxicity remain unknown. Understanding the molecular etiology of oxygen toxicity is key to further improving diving protocols, identifying which divers are at particular risk at high oxygen partial pressures, and predicting potential long-term oxygen toxicity effects among those who show no acute symptoms.In recent studies, simple model systems consisting of lipid bilayers in the form of giant unilamellar vesicles (GUVs)~cell-sized spherical aqueous compartments each bounded by a single lipid bilayer~ have been used to show that oxidation results in significant changes to the properties of these bilayers, including their permeability to small molecules and their elasticity. This damage to a key structural component of the plasma membrane represents a likely mode by which hyperbaric oxygen exposure damages cells, leading to physiological effects. In the proposed work, the PI will move beyond minimal models of lipid oxidation to explore how oxidation alters the chemistry of lipids in cellular systems and how these alterations change lipid bilayer properties and potentially alter the behavior of membrane proteins. This work will enable direct connections to be drawn between the modified bilayer properties observed in earlier work and the effects of hyperbaric oxidation in living cells. The goal of this proposal is to achieve three interconnected objectives that will reveal how hyperbaric oxidation leads to physiological dysfunction by altering lipid bilayer properties: 1. Quantify changes to lipid composition in cells that have been treated with hyperbaric oxygen and with oxidation systems designed to reproduce the chemical effects of hyperbaric oxygen. 2. Determine how lipid bilayer mechanics and permeability change when bilayer compositions match exactly those of the plasma membranes of cells that have been treated with hyperbaric oxygen. 3. Quantify changes to the functional behavior of key neurotransmitter receptor proteins in lipid bilayers with compositions that match exactly those of the plasma membranes of cells that have been treated with hyperbaric oxygen. This proposal represents a transformative extension of the PI s previous fundamental molecular work to systems with practical physiological relevance. Ultimately, this extension is necessary to not only understand the molecular mechanism of hyperbaric oxygen toxicity but also to develop potential medical interventions (diet, antioxidant therapy, drugs to affect neurotransmitter biology) that will minimize the risk of this phenomenon to Navy personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 12, 2016
- Source ID
- N000141612382
Entities
People
- Noah Malmstadt
Organizations
- Office of Naval Research
- United States Navy
- University of Southern California