FIBROBLAST PROTEOGLYCANS AND CONNECTIVE TISSUE MATRIX

结缔组织是由几个大分子组成的复合体，每个大分子都有自己的 特定的遗传分子特征和生物合成加工。 基质中某一组分的分子缺陷可能导致缺陷 许多水平的相互作用也是因为特定的结合 细胞外分子已经改变，或者是因为反馈调节 生物合成导致了细胞内加工的改变。 其他基质成分的胞外量。假设是为了 在这些实验中被检验的是胶原蛋白代谢改变的结果 在蛋白多糖代谢的继发性改变中，产生结构 结缔组织复合体的功能变化。离体 实验证明，蛋白多糖的类型和浓度可以 特异性地影响胶原纤维的形成。 正常成人真皮产生蛋白多糖的数量和类型 用这些外植体建立的外植体和皮肤成纤维细胞系 将被确定，以便为这些项目提供基线 调查。数量、类型、定位、标记动力学和 将比较这些正常细胞产生的蛋白多糖的周转率 对患者的细胞进行类似的测定，这些患者的特定基因 I型或III型胶原结构和代谢缺陷 与胶原和结缔组织分泌减少有关 疾病(成骨不全和Ehler-Danlos综合征， )。由这些物质产生的不溶基质的形态 培养中的细胞将通过免疫荧光显微镜和 电子显微镜。此外，还将检查蛋白多糖的代谢。 在正常人和患者的真皮外植体培养中 确定培养中注意到的变化是否也存在于 细胞在它们的组织环境中。如果没有发现差异，它将 意味着胶原蛋白的生物合成和运输途径 蛋白多糖是分开的，产生改变的胞外比率 这些可能影响基质结构的大分子。如果 蛋白多糖代谢在胶原缺陷的细胞中发生改变，一些 将指出这些分子的共同调节类型。增加了 胶原蛋白与蛋白多糖关系的研究进展 调节功能性结缔组织基质的形成将是 有助于了解伴随着结缔组织的变化 更常见的情况，如正常衰老。

Connective tissue is a complex of several macromolecules, each with its own specific inherited molecular characteristics and biosynthetic processing. A molecular defect in one component of the matrix could lead to defective interactions at many levals either because specific binding between extracellular molecules has been altered or because feedback regulation of biosynthesis has resulted in alterations of the intracellular processing and extracellular quantity for other matrix components. The hypothesis to be tested in these experiments is that altered collagen metabolism results in secondary alterations in proteoglycan metabolism, producing structural and functional changes in the connective tissue complex. In vitro experiments have demonstrated that proteoglycan type and concentration can specifically influence collagen fibrillogenesis. The quantity and type of proteoglycans produced by normal adult dermal explants and skin fibroblast cell lines established from these explants will be determined, in order to provide the baseline for these investigations. The quantity, type, localization, labeling kinetics and turnover of proteoglycans produced by these normal cells will be compared with similar determinations for cells from patients for whom a specific defect in type I or type III collagen structure and metabolism has been associated with decreased secretion of that collagen and connective tissue disease (osteogenesis imperfecta and Ehlers-Danlos syndrome, respectively). The morphology of the insoluble matrix produced by these cells in culture will be described by immunofluorescence microscopy and by electron microscopy. In addition, proteoglycan metabolism will be examined in dermal explant cultures from normal and affected individuals in order to determine whether the alterations noticed in culture are also found in cells in their tissue environment. If no differences are found it will mean that the biosynthetic and transport pathways for collagen and proteoglycans are separate, producing an altered extracellular ratio for these macromolecules that could influence matrix structure. If proteoglycan metabolism is altered in cells with the collagen defects, some type of co-regulation of these molecules will be indicated. Increased understanding of the relationship between collagen and proteoglycans in regulating the formation of a functional connective tissue matrix will be useful in understanding the alterations of connective tissue that accompany much more common conditions, such as normal aging.