Disruption of the plasma membrane's lipid bilayer structure with subsequent loss of its transport barrier function is the mechanism of tissue death in trauma, muscular dystrophies, reperfusion injuries and common diseases. Plasma membrane breakdown is followed by rapid metabolic energy exhaustion, then acute cellular necrosis. It is now well established that certain biocompatible multiblock copolymer surfactants, especially poloxamer 188, are effective in sealing of disrupted cell membranes and can prevent acute necrosis if delivered within a few hours after injury. (Appendix A). It is likely that P188 will soon be a standard component of trauma resuscitation fluids and will have a broad impact on medicine therapeutics. However, P188 may not be the ideal surfactant for membrane repair. It is rapidly degraded by oxygen free radicals into fragments that can be cytotoxic. Thus, it is necessary to determine the intermolecular interactions responsible for surfactant sealing of disrupted membranes so that more stable multiblock copolymer surfactants that seal membranes can be developed. We will test the prevailing hypothesis that sealing surfactants that seal bilayer lipid membranes do so by altering interfacial water structure, thus reducing membrane tension, which then permits reorganization of membrane lipids into a lipid bilayer. We will use established methods (Appendix C) to measure membrane tension while perturbing water structure around permeabilized membranes. The threshold membrane tensions for sealing will be determined for at least two different cell types. We plan to determine sealing efficacy as function of copolymer surfactant structure and determine suitable size of hydrophobic and hydrophilic moieties. We will also perform high resolution measurements of membranes structure and mechanical properties, before and after sealing (Appendix E). Finally, we will conduct studies in parallel to determine if surfactant rescued cells manifest normal phenotype during proliferation or exhibit effects of mutations caused by unrepaired DMA. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064757-06
Application #
7482465
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Somers, Scott D
Project Start
2002-04-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$311,464
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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