MOLECULAR STUDIES IN THE SKELETAL DYSPLASIAS

描述（申请人提供）： 拟议工作的主要目标是利用联系研究， 电子克隆，分离软骨中表达的新基因， 确定病因不明的骨软骨发育不良中的疾病基因。 将产生转基因小鼠模型以阐明病因学和 特定骨软骨发育不良表型的结构/生化基础。 通过这些研究，我们将确定正常功能的决定因素 疾病基因和它们的产物。具体的实验目标 本文拟开展的工作有：1.骨软骨发育不良位点和疾病的定义 由于家庭是通过外联工作和转介到 国际骨骼发育不良登记处，候选基因和 将使用全基因组标记来确定染色体位置， 随后的身份，新的骨软骨发育不良疾病基因; 2. 骨软骨发育不良新候选致病基因的鉴定。我们 将挖掘我们的人胎儿软骨cDNA文库， cDNA克隆作为连锁研究的补充。图书馆还将 作为候选疾病基因的来源， 2.在子项目内部和外部;小鼠模型的生成 骨软骨发育不良这些研究的目的是创造独特的 已知在软骨生物学中起作用的基因突变， 骨软骨发育不良表型。在短期内， 这项研究的目标将直接使有条件的家庭受益， 正在研究提供更早和更具体的诊断（包括 产前诊断），从而改善管理和护理。在较长 术语，每个基因的结构和表达的特征，以及 产生每种疾病的缺陷的性质，可能会建议合理的 治疗方法。最后，这些研究将被整合到一个 更全面地了解软骨细胞的生物学和 定义了软骨细胞外的结构和功能 矩阵

Description (provided by applicant): The principal objectives of the proposed work are to use linkage studies, in silico cloning, and the isolation of novel genes expressed in cartilage, to identify the disease genes in osteochondrodysplasias of unknown etiology. Transgenic mouse models will be generated to elucidate both the etiology and structural/biochemical basis of specific osteochondrodysplasia phenotypes. Through these studies, we will identify the determinants of normal function for the disease genes and their products. The specific experimental goals of the proposed work are: 1. Definition of osteochondrodysplasia loci and disease genes As families are identified by outreach efforts and by referral to the International Skeletal Dysplasia Registry, a combination of candidate gene and genome-wide markers will be used to determine the chromosomal locations, and subsequently the identities, of novel osteochondrodysplasia disease genes; 2. Identification of new candidate disease genes for osteochondrodysplasias. We will mine our human fetal cartilage cDNA library for novel, cartilage-specific cDNA clones as a complement to the linkage studies. The library will also serve as a source of candidate disease genes for collaborative efforts both within and beyond the subproject; 2. Generation of mouse models for the osteochondrodysplasias. The goal of these studies is to create unique mutations in genes known to play a role in cartilage biology to reveal novel osteochondrodysplasia phenotypes. Over the short term, the accomplishment of the goals of this study will directly benefit families with the conditions under study in providing earlier and more specific diagnosis (including prenatal diagnosis), and thereby improved management and care. Over the longer term, the features of the structure and expression of each gene, as well as the nature of the defects that produce each disease, may suggest rational approaches to therapy. Finally, these studies will then be integrated into a more complete understanding of the biology of the chondrocyte and the elements that define the architecture and function of the cartilage extracellular matrix.