The purpose of this program is to bring together several independent investigator so that they can take advantage of an unusual opportunity both to advance the basic information we have about the biology of connective tissues and to explore the possible implications that this information may have for our understanding of diseases which affect these tissues. A major part of the work on diseases will focus on the relatively well-defined genetic diseases osteogenesis imperfecta and Ehlers-Danlos syndrome. These diseases will be studied both because of their own intrinsic importance and because of the implications that several recent discoveries about these diseases have for more common conditions such as osteoporosis, osteoarthritis, and related disorders. The research will include collaborative studies in the following specific areas: Studies on the enzymes which leave the N-terminal propeptide in the conversion of procollagen to collagen and studies on the enzyme which cleaves the C- terminal propeptide in the conversion of procollagen to collagen; formation of collagen fibers in vitro by the enzymatic cleavage of procollagen; structure and function of altered procollagens synthesized by fibroblasts from patients with osteogenesis imperfecta and related disorders; and mutation in genes for type I procollagen in patients with osteogenesis imperfecta and related disorders. Human subjects are used in this work only in the sense that we receive cultured fibroblasts or skin biopsy samples either from repositories (especially the Medical Research Institute in Camden and the ATCC in Bethesda) and from physicians at a large number of hospitals in this country and abroad. Also, one of the enzymes we are studying is prepared from normal, full-term placentas. We use warm-blooded animals in the sense that we prepare antibodies by injecting antigens we have purified into rabbits. Also, we inject isolated collagen genes into mouse embryos to generate transgenic mice. These experiments will be carried out in collaboration with Dr. Robert Brent and in the Stein Laboratory of the Department of Pediatrics. (We understand Dr. Brent has filed a separate application to this committee for the experiments on transgenic mice.)
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