TRANSGENIC MOUSE MODEL OF OSTEOGENESIS INPERFECTA TYPE I

成骨不全I型(OI I)是一种轻微的、以遗传为主的 以骨骼和结缔组织脆性为特征的疾病 耳聋。I型胶原的突变是所有已知病例的原因。它 之前曾假设，人类基因组中的杂合子零突变 Alphal(I)型胶原基因在这种类型的OI中占主导地位。(按使用情况 在这里，零突变会导致总胶原蛋白产量的下降。) 然而，OI I表型的分子基础在很大程度上是未知的， 而疾病的发病机制仍然知之甚少。幸运的是， 杂合子零字母(I)胶原等位基因的作用可以研究 在转基因小鼠品系Mov13中。一种小鼠逆转录病毒的整合 在Alphal(I)胶原基因内导致零等位基因受阻于 转录水平。培育出只有一个零等位基因的Mov13小鼠 产生的α(I)胶原基因和蛋白比正常减少50%。我们 最近证明，Mov13小鼠的组织中含有 I型胶原蛋白显著减少，突变小鼠的I型胶原蛋白 骨骼和结缔组织脆弱，耳聋。因此，Mov13小鼠 作为研究OI发病机制的模型。 这一提议的假设是，基因介导的减少 I型胶原导致骨骼脆性。实验设计 是由研究人员与生物学家之间独特的合作推动的 和工程背景，并将利用遗传学、生物化学和 生物力学工程学。这项提案的长期目标是使用 Movl3突变以深入了解I型的贡献 胶原蛋白对骨骼的结构和功能有促进作用。这项提案有两个 具体目标：首先，记录骨骼表型的演变 随着Mov13小鼠年龄的增长和第二次，研究 骨骼缺陷可以通过药物治疗和/或通过 基因操纵。

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.