The Interdisciplinary Basic Research in Dermatology program proposes research that will expand the understanding of the structure, composition and function of normal skin using as models and research material the tissue, cells and skin-derived molecules from patients with inherited disorders of the epidermis, dermis and dermal-epidermal junction (DEJ). A further goal is to identify the molecular basis for certain inherited disorders of skin. The program consists of 5 projects and 3 cores. Biochemical methods, transient transfection of cultured keratinocytes and transgenic animals will be used in project 1 (Dale) to understand the expression, biosynthesis and function of filaggrin in its interaction with keratins in normal individuals and those affected with diseases of keratinization. Epidermal differentiation is also a theme of the research in project 4 (Fleckman). Mechanisms of abnormal (reduced or absent) profilaggrin expression in patients with ichthyosis vulgaris will be investigated in order to learn more about normal expression, and to determine the molecular basis of this disease. The goal of project 6 (Stephens) is to map the gene responsible for the Weber-Cockayne subtype of epidermolysis bullosa (EB) simplex with the long term goal of cloning c)the gene and understanding the pathobiology of this form of the disease. Project 7 (Carter) will test the hypothesis that compromised adhesion at the dermal-epidermal junction in the skin of patients with junctional and simplex forms of EB are a consequence of mutations in adhesion receptors, ligands and associated cytoskeletal components. The research proposed in project 8 (Byers) will elucidate the molecular basis of disorders of collagen gene structure and synthesis in humans that result in forms of the Ehlers-Danlos syndrome in order to reveal how those mutations alter the structure and function of molecules that incorporate the abnormal chains and result in the disease phenotype. Three cores will provide collaboration and service to the investigators. The Morphology Core Laboratory (Holbrook) will provide histologic and ultrastructural examination of skin, cells and molecules for all projects. The Keratinocyte Culture Core (Fleckman) will grow (and bank) normal and pathologic keratinocytes and fibroblasts for the investigators in projects 1, 4 and 6 (primarily), and the Molecular Genetics Core (Stephens) will provide clinical diagnosis and collection of tissue from patients with keratinization and bullous diseases, construct immortalized lymphoblastoid cell lines, identify and characterize DNA polymorphisms, and assist in linkage analyses and DNA sequencing.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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University of Washington
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Bunick, Christopher G; Presland, Richard B; Lawrence, Owen T et al. (2015) Crystal Structure of Human Profilaggrin S100 Domain and Identification of Target Proteins Annexin II, Stratifin, and HSP27. J Invest Dermatol 135:1801-1809
Chan, Aegean; Godoy-Gijon, Elena; Nuno-Gonzalez, Almudena et al. (2015) Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses. JAMA Dermatol 151:285-92
Mitchell, Anna L; Judis, LuAnn M; Schwarze, Ulrike et al. (2012) Characterization of tissue-specific and developmentally regulated alternative splicing of exon 64 in the COL5A1 gene. Connect Tissue Res 53:267-76
Chatterjea, Sudeshna M; Resing, Katheryn A; Old, William et al. (2011) Optimization of filaggrin expression and processing in cultured rat keratinocytes. J Dermatol Sci 61:51-9
Mitchell, Anna L; Schwarze, Ulrike; Jennings, Jessica F et al. (2009) Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum Mutat 30:995-1002
Abrass, C K; Berfield, A K; Ryan, M C et al. (2006) Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene. Kidney Int 70:1062-71
Kelsell, David P; Norgett, Elizabeth E; Unsworth, Harriet et al. (2005) Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet 76:794-803
Pirrone, Annalisa; Hager, Barbara; Fleckman, Philip (2005) Primary mouse keratinocyte culture. Methods Mol Biol 289:3-14
Presland, Richard B; Fleckman, Philip (2005) Tetracycline-regulated gene expression in epidermal keratinocytes. Methods Mol Biol 289:273-86
Frank, Diane E; Carter, William G (2004) Laminin 5 deposition regulates keratinocyte polarization and persistent migration. J Cell Sci 117:1351-63

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