Molecular mechanisms and pathways for gas transport across biological membranes and implications for physiology and performance MURI 2016
Abstract
One of the most fundamental processes in life and disease is gas transport across biological membranes, which are lipid bilayers impregnated with proteins. Previously it was believed that all gases cross all membranes simply by dissolving in and diffusing through the lipid portion of the membrane. This changed when Dr. Boron discovered (a) a biological membrane impermeable to CO2, and (b) a membrane protein permeable to CO2. This protein~Aquoaporin 1 (AQP1)~became the first known gas channel. Since then, our evolving understanding is that gases cross biological membranes via two major routes: 1) membrane lipids and 2) a subset of membrane proteins ~ gas channels. Other membrane proteins that are not gas permeant ~ blocking proteins - displace membrane lipids and may form a partial barrier that restricts access to the lipid bilayer. Gas permeability depends not only on the identity of the gas but also on (a) membrane lipid composition; (b) the identity and abundance of blocking proteins; and (c) the identity and abundance of individual gas channels. All three parameters depend on cell type and probably on physiological/pathological status. Lipid composition also depends on diet and medication. Despite progress, our knowledge remains rudimentary. To establish a molecular mechanism of gas permeation and implications for performance, the PI has assembled a multidisciplinary team: Walter Boron (PI) at Case Western Reserve University, Emad Tajkhorshid at University of Illinois, Noah Malmstadt at University of Southern California, and Ardi Vahedi-Faridi at Case Western. The team~s expertise includes structural biology, molecular dynamics, molecular biology, reconstitution of recombinant proteins into synthetic membranes, electrophysiology, stopped-flow spectroscopy, proteomic and lipidomic collaborations, genetic manipulation of mice, assessment of exercise performance. As a group, they will focus on three important gases (O2, CO2, NH3), lipids important for RBCs and other mammalian cell membranes (including cholesterol and sphingolipids), and representatives of three channel families (AQPs, Rh proteins, GLUTs). The approach will be iterative~moving from the level of atoms to animals and back again.The proposed research represents a quantum leap for the field of gas channels, itself a major paradigm shift in biology. The research aims to totally reorganize the understanding of how gases cross membranes, and link molecular mechanism to whole-animal performance. These studies are highly relevant for the DoD missions (e.g., decompression illness, gas toxicity, acute mountain sickness, exercise performance, wound healing), and to the general public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 30, 2016
- Source ID
- N000141612535
Entities
People
- Walter Boron
Organizations
- Case Western Reserve University
- Office of Naval Research
- United States Navy