COLLAGEN BIOSYNTHESIS IN CONNECTIVE TISSUE DISEASE

胶原蛋白是人体的主要结构蛋白，因此可以提供 所有组织的框架，包括皮肤，骨骼，肌腱，软骨， 肺、角膜和心脏瓣膜。正确的胶原蛋白生物合成需要 精确协调多个转录和翻译后工作 步骤包括调节特定类型的胶原生物合成， 脯氨酸和赖氨酸的羟基化，羟赖氨酸的糖基化， 二硫键的形成，运输到胞外空间，酶促 延伸肽的切除、原纤维的形成和交联。 这种顺序生物合成方案中的扰动可能会被预期 导致结缔组织结构改变和疾病。个体 已有患者描述了胶原生物合成的异常。 临床表现为Ehler-Danlos综合征，成骨不全， 还有皮肤松弛。我们建议研究皮肤中胶原的生物合成。 从这些研究胶原生物合成的患者身上获得的成纤维细胞 从这些和其他遗传性疾病患者身上获得的皮肤成纤维细胞 结缔组织紊乱。胶原蛋白的以下参数 生物合成将被测量：(1)特定类型的胶原合成，(2) 前胶原的合成及加工，(3)前胶原的合成 糖基化羟基赖氨酸，(4)可还原交联物的合成，(5) 赖氨酰羟基酶、赖氨酸羟基酶和赖氨酸羟基酶水平，(6) (7)胶原基因的结构。希望是这样的 这些研究将使我们能够更好地了解这些疾病 生化水平。这样的理解是理性的前提 产前诊断、遗传咨询和治疗管理。

Collagen is the major structural protein of the body and as such provides the framework for all tissues including skin, bone, tendon, cartilage, lung, cornea, and heart valve. Proper collagen biosynthesis requires a precise orchestration of a number of transcriptional and post-translation steps including regulation of type-specific collagen biosynthesis, hydroxylation of proline and lysine, glycosylation of hydroxylysine, disulfide bond formation, transport to the extracellular space, enzymatic excision of extension peptides, fibril formation, and cross-linking. Perturbation in this sequential biosynthetic scheme might be expected to result in structurally altered connective tissue and disease. Individual abnormalities in collagen biosynthesis have been described in patients presenting clinically with Ehlers-Danlos syndrome, osteogenesis imperfecta, and cutis laxa. We propose to study collagen biosynthesis in skin fibroblasts obtained from patients with these study collagen biosynthesis in skin fibroblasts obtained from patients with these and other inherited disorders of connective tissue. The following parameters of collagen biosynthesis will be measured: (1) type-specific collagen synthesis, (2) synthesis of procollagen and processing of procollagen, (3) synthesis of glycosylated hybroxylysine, (4) synthesis of reducible cross-links, (5) levels of lysyl hydroxylase prolyl hydroxylase and lysyl, (6) levels of collagen specific mRNA, and (7) structure of collagen genes. It is hoped that these studies will allow us to better understand these diseases at a biochemical level. Such understanding is a prerequisite for rational prenatal diagnosis, genetic counseling, and therapeutic management.