MOLECULAR GENETICS OF SKIN BASEMENT MEMBRANE ZONE

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The present proposal is submitted in response to research grants announcement in the area of epidermolysis bullosa (EB) and basement membrane zone biology. The proposed studies are designed to test the hypothesis that mutations in the genes that code for the matrix structural macromolecules of the basement membrane zone in skin cause one or more forms of EB. The proposal entails concentrated, multidisciplinary studies performed by experts representing different scientific disciplines and all now participating in collaborative research within the Jefferson Institute of Molecular Medicine. The five component projects are highly interdependent. Project 1, "Clinical and Ultrastructural Studies," will provide the essential patient material and critical clinical information on the patients, the morphological changes in the skin, and the distribution of specific antigens that will guide work on the other projects. The data generated in Project 2, "Use of Restriction Fragment Length Polymorphism for Linkage Studies," are vital to ruling in or ruling out specific genes and alleles as candidates for mutations that will be explored in greater detail in Projects 3 and 4. Project 3, "Genetic Defects in the Biosynthesis of Basement Membrane Zone Macromolecules," will provide information on the gene-protein systems that may be at fault in various forms of EB. The work on this project, primarily concentrating on elucidation of structural alterations in basement membrane zone macromolecules at the protein and mRNA level, will thus provide necessary information about mutations that will be explored in detail on Project 4. Project 4, "Mutations in Genes Expressed in Skin," will use the techniques of molecular biology to define precisely the gene mutations. Such information will then provide a basis for definitive classification of the variants of EB identified in Projects 1, 2 and 3. Project 5, "New Clones and Structures for Genes Expressed in Skin," will provide additional gene probes and information about the normal gene structures that are essential for studies in Projects 2, 3, and 4. These multidisciplinary studies are expected to provide precise information on the underlying molecular defects in various forms of EB. Such information is of critical importance in developing definitive classifications for this disease, for development of prenatal diagnostic tests, and to provide a basis for developing therapeutic approaches for this disease. In addition, the projects will generate materials, technologies and information that can serve as a permanent resource for future studies on EB and other heritable diseases affecting skin.