Anchoring fibrils, composed of type VII collagen (C7), are critical for epidermal-dermal adherence. Both genetic and autoimmune disorders targeting C7 result in chronic, incurable blistering diseases. Dystrophic Epidermolysis Bullosa (DEB), due to mutations in the gene that encodes for C7 (COL7A1) may be inherited in a dominant or recessive (RDEB) pattern. An acquired form of DEB, epidermolysis bullosa acquisita (EBA), is caused by IgG autoantibodies to C7 which perturbs the function of anchoring fibrils. Our overall goal is to understand the structure and function of C7 and anchoring fibrils. Biochemical methods could not provide enough purified C7 to do this work. We solved this problem by using a molecular biology approach and can now make milligram quantities of purified C7 and various domains and sub-domains allowing us to carry out extensive structure and function studies. We can transfect wild type COL7A1 or any published DEB mutation into C7-null cells and create C7 molecules that reflect a given DEB gene defect. Likewise, we can create DEB cells that reflect the biology of cells from DEB patients. We also have an in vivo human skin equivalent model to examine the quantity and quality of anchoring fibrils in designer skin equivalents made from RDEB cells, RDEB gene-corrected cells or designed gene-defective cells. We also developed a new murine model for EBA and directly demonstrated the pathogenic activities of human and rabbit anti-C7 autoantibodies. In this proposal, using these novel reagents, we will study the structure and function of RDEB C7 molecules including matrix and cell binding sites, exportation from their cell of origin, resistance to protease digestion, triple helix and anti-parallel dimer formation, disulfide bonding and the formation of anchoring fibrils in vivo. We will create RDEB cells harboring COL7A1 mutations known to result in the production of an abnormal C7 and examine the cell biology of designer DEB cells. We will define for the first time the "pathogenic" versus "marker non-pathogenic" segments of C7 using our newly developed murine EBA model. By immunoabsorption of anti-C7 antibodies against domains and sub-domains of C7, we will determine the smallest pathogenic EBA epitopes on C7 and evaluate the feasibility of peptide epitope decoy therapy for EBA. Lastly, we found that C7 strongly promotes keratinocyte migration and markedly accelerates wound closure when delivered to murine and human skin wounds. We will identify the C7 domains that are essential for promoting wound closure and reveal the molecular mechanisms by which C7 promotes wound healing.

Public Health Relevance

Type VII (anchoring fibril) collagen (C7) in skin can be perturbed by a heritable gene defect or by an acquired autoantibody against it, both of which cause incurable scarring blistering skin diseases. We will elucidate the structure and function of C7 and determine how perturbations of C7 cause skin blisters and how C7 promotes wound closure. The proposed studies will facilitate developing effective therapy for devastating skin diseases and chronic non-healing wounds.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-H (02))
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Baker, Carl
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Cogan, Jon; Weinstein, Jacqueline; Wang, Xinyi et al. (2014) Aminoglycosides restore full-length type VII collagen by overcoming premature termination codons: therapeutic implications for dystrophic epidermolysis bullosa. Mol Ther 22:1741-52
Woodley, David T; Cogan, Jon; Wang, Xinyi et al. (2014) De novo anti-type VII collagen antibodies in patients with recessive dystrophic epidermolysis bullosa. J Invest Dermatol 134:1138-40
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