TRANSGENIC MOUSE MODEL OF OSTEOGENESIS INPERFECTA TYPE I

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Osteogenesis imperfecta type I (OI I) is a mild, dominantly inherited disorder characterized by bone and connective tissue fragility and deafness. Mutations in type I collagen account for all known cases. It was hypothesized previously that heterozygous null mutations in the alphal(I) collagen gene would predominate in this form of OI. (As used here, null mutations cause a decrease in total collagen production.) However, the molecular basis of the OI I phenotype is largely unknown, and disease pathogenesis remains poorly understood. Fortunately, the effects of a heterozygous null alphal(I) collagen allele can be studied in the transgenic mouse strain Movl3. Integration of a murine retrovirus within the alphal(I) collagen gene results in a null allele blocked at the level of transcription. Movl3 mice bred to have only one null allele produce 50% less alphal(I) collagen mRNA and protein than normal. We recently demonstrated that the tissues of Movl3 mice contain significantly less type I collagen than normal and that mutant mice have bone and connective tissue fragility and are deaf. As such, Movl3 mice serve as a model to investigate the pathogenesis of OI I. The major hypothesis of this proposal is that a genetically-mediated decrease in type I collagen results in skeletal fragility. The experimental design is driven by a unique collaboration between investigators with biological and engineering backgrounds and will utilize genetics, biochemistry, and biomechanical engineering. The long term goal of this proposal is to use the Movl3 mutation to gain insight into the contribution made by type I collagen to the structure and function of bone. The proposal has two specific aims: first, to document the evolution of the skeletal phenotype as Movl3 mice age and second, to investigate the possibility that the skeletal defect can be ameliorated by pharmacological treatment and/or by genetic manipulation.