EXCEED THE SPACE PROVIDED. Epidermolysis bullosa (EB)is an inherited blistering disease of the skin and mucous membranes, with an estimated incidence of 100,000 in the United States. EB can be classified into three major groups on the basis of the level of blister formation within the skin. In the dystrophic forms of EB (DEB), the tissue separation occurs below the lamina densa at the level of the anchoring fibrils, which are composed mainly, if not exclusively, of type VII collagen.DEB results from different types and combinations of mutations in the gene encoding type VII collagen, COL7A1.The disease presents with a wide spectrum of clinical severity, and there is no treatment option available. Significant progress has been made by our group and others in the understanding of genotype-phenotype correlations in DEB, however, it is essential to establish an in vitro and an in vivo DDEB model for the study of the functional effects of mutations for the analysis of novel treatments. We hypothesize that a skin model built using cells with a COL7A1 expression pattern identical to that found in the skin of DDEB patients will present the pathological features characteristic of DDEB, and will therefore provide a suitable in vitro model of DDEB. Further, a transgenic mouse model expressing dominant negative mutations in the mouse type VII collagen gene will demonstrate identical impairment of the cutaneous basement membrane zone observed in human DDEB patients, and will therefore provide a suitable animal model for studying the pathology of DDEB and the testing of treatment options in vivo. Finally, based on the growing body of information around the use of ribozyme therapy to selectively cleave target RNA molecules, we hypothesize that target specific hammerhead ribozymes can be used to neutralize the dominant negative effect of mutations underlying DDEB at the mRNA level, and therefore, can be considered a feasible treatment approach for DDEB. PERFORMANCE SITE ========================================Section End===========================================
