CREATION OF THE AD02 MOUSE

描述(申请人提供)：常染色体显性遗传性骨化症，2型(ADO2)是一种骨硬化性疾病，由破骨细胞性骨吸收受损引起。这种疾病通常是由于氯离子通道7基因(CLCN7)的错义突变引起的。疾病的严重程度差异很大，即使在同一个家庭的成员中也是如此，三分之一的突变个体是无症状携带者。我们实验室的体外研究表明，来自无症状携带者的破骨细胞正常地吸收骨，而来自受影响个体的破骨细胞具有明显的骨吸收缺陷。因此，受影响的个体和携带者之间的差异是由于破骨细胞的特性所致。我们的初步数据与不止一个修饰基因导致这种差异是一致的。这项建议的重点是建立ADO2小鼠模型。这种动物模型将使我们能够测试潜在的治疗方法，并找到控制疾病严重程度的基因。摘要：常染色体显性遗传性骨质疏松症(ADO2)是一种骨质致密但脆弱的疾病。疾病的严重程度在携带者(没有疾病)和严重感染的个人之间有所不同，后者有多处骨折、骨感染，偶尔还会失明。这项建议的重点是建立ADO2小鼠模型。这种动物模型将使我们能够测试潜在的治疗方法，并找到控制疾病严重程度的基因。

DESCRIPTION (provided by applicant): Autosomal dominant osteopetrosis, type 2 (ADO2) is an osteosclerotic disorder that results from impaired osteoclastic bone resorption. The disorder usually results from missense mutations in the Chloride Channel 7 gene (CLCN7). Disease severity varies widely, even among members of the same family, and one third of individuals with mutations are asymptomatic carriers. In vitro studies in our laboratory indicate that osteoclasts from asymptomatic carriers resorb bone normally, while those from affected individuals have markedly defective bone resorption. Thus, the difference between affected individuals and carriers is due to osteoclast specific properties. Our preliminary data, are consistent with there being more than one modifier gene that is responsible for this difference. This proposal focuses on the creation of an ADO2 mouse model. This animal model will allow us to test potential therapies and find genes that control disease severity. Lay abstract: Autosomal dominant osteopetrosis (ADO2) is a disease in which there is dense, but fragile bone. The severity of the disease varies between carriers (who are disease free) and severely affected individuals, who have multiple fractures, bone infections and, occasionally, blindness. This proposal focuses on the creation of an ADO2 mouse model. This animal model will allow us to test potential therapies and find genes that control disease severity.