The Skeletal Dysplasias

描述(申请人提供)：骨骼发育不良是一组超过370种疾病，导致不成比例的矮小和/或骨骼畸形。虽然长期以来，它们被认为是软骨内和/或膜性骨化的泛发性疾病，但它们的异质性程度和遗传学基础仍在阐明中，其发病机制现在可以被研究。该计划项目旨在对骨骼发育不良的临床、遗传、形态、生化和分子特征进行多学科研究。具体目标包括：1.扩大国际骨骼发育不良登记处的研究材料。2.定义骨骼发育不良的临床和放射学特征和遗传异质性，并阐明每种疾病的自然病史、生长特点和并发症。3.骨骼发育不良产前诊断方法的改进。4.阐明各骨性发育不良软骨组织的组织学、组织化学、免疫组织学和超微结构特征。5.采用连锁、定位克隆和候选基因的方法，筛选出病因不明的骨软骨发育不良的致病基因。6.每种骨骼发育不良的临床、X线和形态特征与其特定的生化和分子缺陷的相关性。7.开发一种新的蛋白质生物化学核心，以提供专门的分析方法，包括蛋白质质谱学，以表征人类和小鼠骨骼发育不良的蛋白质缺陷。8.评价蛋白质翻译后修饰对软骨发育的影响。该计划项目包括两个核心设施，即国际骨骼发育不良注册中心和蛋白质生物化学核心，以及三个综合项目；(1)临床、病理生理学和治疗研究；(2)骨骼发育不良的分子研究；以及(3)骨骼发育不良的发育研究。国际骨骼发育不良登记处是世界上最大的骨骼发育不良登记处/数据库，是研究骨骼发育不良的国际资源。一个世界范围内的咨询健康专业人员小组为这些研究项目提供了来自临床记录病例的材料，以定义对这些疾病的生物学基础的全面了解。

DESCRIPTION (provided by applicant): The skeletal dysplasias are a group of more than 370 disorders that result in disproportionate short stature and/or skeletal deformities. Although they have long been considered to be generalized disorders of endochondral and/or membranous ossification, the extent of their heterogeneity and genetic basis is still being elucidated and their pathogenesis can now be investigated. This program project is directed toward a multidisciplinary investigation of the clinical, genetic, morphologic, biochemical, and molecular characteristics of the skeletal dysplasias. Specific aims include: 1. Expansion of the materials for study in the International Skeletal Dysplasia Registry. 2. Definition of the clinical and radiographic features and genetic heterogeneity of the skeletal dysplasias and elucidation of the natural history, growth characteristics, and complications of each of these disorders. 3. Improvement of methods for the antenatal diagnosis of prenatal-onset skeletal dysplasias. 4. Elucidation of the histological, histochemical, immunohistological, and ultrastructural characteristics of chondroosseous tissue in each of the skeletal dysplasias. 5. Identification of the disease genes in osteochondrodysplasias of unknown etiology, using linkage, positional cloning, and candidate gene approaches. 6. Correlation of the clinical, radiographic, and morphologic features of each skeletal dysplasia with their specific biochemical and molecular defects. 7. Development of a new Protein Biochemistry Core to provide specialized analytical methods, including protein mass spectrometry, to characterize the protein defects in human and mouse skeletal dysplasias. 8. Evaluation of the effects of post-translational modification of proteins on chondroosseous development. The program project is consisted of two core facilities, the International Skeletal Dysplasia Registry and the Protein Biochemistry Core, plus three integrated projects; (1) Clinical, pathophysiological and therapeutic studies; (2) Molecular studies in the skeletal dysplasias; and (3) Developmental studies in the skeletal dysplasias. The International Skeletal Dysplasia Registry, the largest such registry/database in the world, serves as an international resource for studying the skeletal dysplasias. A worldwide group of referring health professionals provide materials from clinically documented cases for these research projects are integrated to define a comprehensive understanding of the biological basis of these conditions.