The broad, long-term objective of this proposal is to understand the structure and function of the lamellar lipid assemblies that form the epidermal permeability barrier and govern the normal exfoliation and replacement of the epidermal surface cells. Several of the most common skin diseases, including psoriasis, ichthyoses, seborrheic dermatitis, dry skin, and acne, are thought to involve these epidermal lipid systems. Of particular interest, and presumed biological importance, is the recently discovered lipid sheath that is chemically attached to the outer ; I protein surface of each individual horny cell. It is proposed to determine the manner in which this lipid envelope is assembled, and to define the properties of the protein to which it becomes attached. Assembly of the precursor-molecules of the lipid envelope in their final location on the cell surface will be investigated by isolation and characterization of lamellar body bounding membranes that are directed to the epidermal cell surface during its final development. The protein to which the lipids become attached may be involucrin, which is known to contain the high proportion of glutamate residues necessary for linkage to the hydroxyceramides that constitute the corneocyte lipid envelope. The proportion of glutamate residues in the cross-linked protein envelope will be examined by solid state nuclear magnetic resonance techniques. The degree to which additional glutamate residues are provided by hydrolysis of glutamines will be studied by both chemical and NMR methods. Studies of the non-bound intercellular lipids, which constitute the water barrier in the stratum corneum, are aimed at determining how the unique lamellar patterns are produced and how they contribute to epidermal function. This will involve in vitro emulation of the succession of morphologic changes of lipid assemblies involved in epidermal cell differentiation, by manipulating the lipid composition of synthetic bilayer systems. Interactions within and between the intercellular lamellae and the corneocyte lipid envelopes will also be examined by biophysical and NMR techniques.
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