The long term goal of this project is to define the lipid molecule arrangements necessary for cell membrane fusion. The focus is on understanding the molecular details of the fusion of model lipid membranes with as mediated by poly(ethylene glycol) [PEG]. The information obtained will advance PEG-mediated cell fusion technologies and provide insight into how proteins mediate fusion of cell membranes. PEG acts to bring model membranes into close contact by removing the water between them. Biomolecular leaflets of lipids organized into closed vesicular structures serve as models for cell membranes. The Lentz group has shown that disrupted molecular packing in the contacting monolayers of lipid bilayers will induce membrane fusion. The time course of the ensuing fusion process has also been defined and shown to bear remarkable similarity to the sequence of events observed in viral membrane fusion and secretory granule fusion, except that many more molecular details can be defined in the model membrane experiments carried out by the Lentz group. Dr. Lentz plans now to define molecular details as they occur in fusion of PEG-aggregated model membranes and to compare the model membrane process with what is known about biomembrane fusion in order to test the hypothesis that these two processes share molecular mechanisms. This will involve three specific aims: 1] define and compare the kinetics of model and biomembrane fusion; 2] define the lipid structural rearrangements that occur during fusion; and 3] determine how membrane structural perturbations might alter the fusion process. In addition, Dr. Lentz will test whether peptide fragments from the fusion proteins of lipid-sheathed viruses (in this case, influenza; others include human and simian immunodeficiency virus) will disrupt bilayers in ways that enhance membrane fusion.
Three specific aims will also be addressed here: 1] define the effects of viral fusion peptide on model membranes and on their PEG-mediated fusion; 2] test whether lipid packing disruption is critical to allow peptide to bind to membranes in a fusion-inducing conformation; and 3] determine how the influenza viral fusion peptide might alter membrane structure so as to encourage one of more steps in the fusion process.
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