PATHOLOGY OF INBORN SKELETAL DISEASES

该项目在蛋白质水平上定义了 导致骨骼疾病的胶原代谢遗传性紊乱。 目的是了解胶原基因突变的后果 在表达的蛋白质结构和改变的大分子 细胞外基质中的相互作用。具体目标包括 了解II型胶原蛋白缺陷的分子效应， 包括由单个碱基变化引起氨基酸取代， 和由剪接位点突变引起的部分外显子缺失。规则 潜在基因缺陷、表达蛋白 将探索异常、组织病理学和临床表型。 胶原蛋白分子翻译后化学的变化 突变链，即脯氨酸羟基化，赖氨酸羟基化， 羟基赖氨酸糖基化和分子间交联将 研究，追求一个假设，这种次要的质量 变化是临床表型和疾病的重要决定因素 严重性。该方法是将方法应用于蛋白质分析（肽 映射和气相测序适合的特殊功能， 胶原化学）应用于人体组织样本。定义病例的组织 软骨发育不良，包括软骨发育不全/软骨发育不良， 脊椎骨骺发育不良（SED），脊椎骨骺发育不良 （SEMD）、最严重的发育不良和家族性骨关节病/轻度SED将被 研究了IX、X和Xi型胶原蛋白中蛋白质水平的缺陷将 也可以使用类似的方法在细胞外基质中寻找。的 Ehlers-Danlos综合征VI中胶原交联缺陷的性质 将被追捕。骨基质胶原病理的共同特征 在成骨作用中，也将在蛋白质水平上探索骨钙素。的 这项工作的意义是公开的集体的重大影响， 遗传性骨骼疾病，以及相关的轻度突变， 基因多态性，强烈怀疑易患 常见的骨骼老化、骨质疏松症和骨关节炎。 随着生活质量和医疗保健服务负担的增加， 骨骼的退化性疾病，了解分子基础 如果有效，这些遗传因素的流行是必不可少的 将采取诊断、预防和治疗战略。

This project is defining at the protein level the molecular basis of heritable disorders of collagen metabolism that cause skeletal disease. The goal is to understand the consequences of mutations in collagen genes in terms of expressed protein structure and altered macromolecular interactions in the extracellular matrix. The specific aims include understanding the molecular effects of type II collagen defects that include amino acid substitutions caused by single base changes and full and partial exon deletions caused by splice site mutations. Rules in the relationship between underlying gene defect, expressed protein abnormality, tissue pathology and clinical phenotype will be explored. Changes in post-translational chemistry of collagen molecules bearing mutant chains, that is in proline hydroxylation, lysine hydroxylation, hydroxylysine glycosylation and intermolecular cross-linking will be examined, pursuing an hypothesis that the quality of such secondary changes are important determinants of the clinical phenotype and disease severity. The approach is to apply methods in protein analysis (peptide mapping and gas-phase sequencing adapted for the special features of collagen chemistry) to human tissue specimens. Tissues from defined cases of chondrodysplasia including achondrogenesis/hypochondrogenesis, spondyloepiphyseal dysplasia (SED), spondyloepimetaphyseal dysplasia (SEMD), Kniest dysplasia and familial osteoarthrosis/mild SED will be studied. Defects at the protein level in collagen types IX, X and XI will also be sought in the extracellular matrix using a similar approach. The nature of the collagen cross-linking defect in Ehlers-Danlos syndrome VI will be pursued. Common features of the pathology of bone matrix collagen in osteogenesis imperfecta will also be explored at the protein level. The significance of the work is the major impact collectively of overt heritable skeletal diseases, and also of related mild mutations and genetic polymorphisms that are strongly suspected to predispose to the common disorders of the aging skeleton, osteoporosis and osteoarthritis. With the increasing burden in life quality and health care delivery of degenerative disorders of the skeleton, understanding the molecular basis and prevalence of such genetic factors is essential if effective diagnostic, preventive and therapeutic strategies are to be pursued.