TRANSGENIC MOUSE MODEL OF OSTEOGENESIS INPERFECTA TYPE I

成骨细胞I型（OI I）是一种温和的，显性遗传的 以骨和结缔组织脆性为特征的疾病， 耳聋 I型胶原蛋白的突变解释了所有已知的病例。 它 以前假设，在基因组中的杂合无效突变， 在这种形式的OI中，I型胶原基因占主导地位。(As使用 在此，无效突变导致总胶原蛋白产生的减少。 然而，OI I表型的分子基础在很大程度上是未知的， 并且疾病的发病机理仍然知之甚少。 好在 可以研究杂合的无效型胶原（I）等位基因的作用， 在转基因小鼠品系Movl 3中。鼠逆转录病毒的整合 胶原蛋白（I）基因中的一个无效等位基因被阻断， 转录水平。 繁殖为仅具有一个无效等位基因的Movl 3小鼠 产生比正常少50%的胶原（I）mRNA和蛋白质。 我们 最近证明Movl 3小鼠的组织含有 与正常小鼠相比，I型胶原蛋白明显减少， 骨骼和结缔组织脆弱，耳聋。 因此，Movl 3小鼠 作为研究OI I发病机制的模型。主要 该建议的假设是，遗传介导的 I型胶原导致骨骼脆弱。 实验设计 是由研究人员与生物学之间的独特合作推动的， 和工程背景，并将利用遗传学，生物化学， 生物机械工程 该提案的长期目标是使用 Movl 3突变，以深入了解I型糖尿病的贡献。 胶原蛋白对骨的结构和功能的影响。 该提案有两个 具体目标：首先，记录骨骼表型的演变 随着Movl 3小鼠年龄的增长，第二，为了研究这种可能性， 骨骼缺陷可以通过药物治疗和/或通过 基因操控

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.