MOLECULAR BIOLOGY OF OSTEOARTHRITIS & CHONDRODYSPLASIAS

本医师科学家奖提案旨在允许候选人 获得分子生物学的基本和高级知识和技能 研究并将其应用于软骨疾病的研究。 细胞与分子生物学和蛋白质生物化学研究生课程 这为未来的研究工作提供了坚实的基础 在这个奖项的第一年。 在第一阶段，人类疾病的转基因小鼠模型， 将产生IX型胶原的α 2链中的突变。 类型 IX胶原是一种软骨特异性分子，具有独特的结构， 这些特征可能使正常软骨所必需的分子 结构和功能。因为II型胶原蛋白的突变 显示导致人类疾病，很可能是类型的异常 IX胶原蛋白也可以。 在α 2（IX）链中有三个或四个突变， 其含有链间二硫键，与II型 胶原蛋白、糖胺聚糖附着位点和扭结区域，将被 构建并产生含有这些突变的转基因小鼠。 异常表型将通过放射学表征， 显微镜下。 在第二阶段，这些突变改变正常细胞的机制 将寻求软骨的发育、结构和功能。 在 同时，各种结构-功能关系的信息 将获得IX型分子的结构域。 奖项的这一阶段 将准备候选人的分子遗传学的进一步研究 人类软骨疾病。

This Physician Scientist Award proposal is designed to permit the candidate to acquire basic and advanced knowledge and skills in molecular biologic investigation and to apply these to the study of cartilage diseases. Graduate coursework in cell and molecular biology and protein biochemistry which provide a firm basis for future research endeavors will be taken during the first year of this Award. During Phase I, transgenic mouse models of human disease, containing mutations in the alpha2 chain of type IX collagen, will be generated. Type IX collagen Is a cartilage-specific molecule with unique structural features that likely render the molecule necessary for normal cartilage structure and function. Because mutations in type II collagen have been shown to cause human disease, it is quite likely that abnormalities of type IX collagen do also. Three or four mutations in the alpha2 (IX) chain, which contains interchain disulfide bridges, crosslink sites to type II collagen, a glycosaminoglycan attachment site and a kink region, will be constructed and transgenic mice containing these mutations generated. Abnormal phenotypes will be characterized radiographically and microscopically. During Phase II, mechanisms by which these mutations alter normal development, structure and function of cartilage will be sought. At the same time, information on the structure-function relationship of various domains of the type IX molecule will be obtained. This phase of the Award will prepare the candidate for additional studies of the molecular genetics of human cartilage diseases.