REGULATED ASSEMBLY OF THE EXTRACELLULAR MATRIX

描述（改编自申请人的摘要）：胶原蛋白稳定 大多数器官的结构。 申请人已经证明， 最初组装成离散的原纤维片段。 这些段 在发育中的细胞外 矩阵 随着发育的进行， 发生。 这涉及到内部中间体（段）的转换 未成熟的组织变得更长，并且在大多数组织中，直径更大 原纤维（肌腱）;直径不变的更长原纤维（角膜）; 或者可能是持续的节段（快速重塑）。 相对于该 应用程序，假设片段经历沉积后 融合，随后是分子重排， 成熟组织的原纤维。 这一假设预测了细分市场的变化 纤维形成过程中的结构是由片段组装成纤维 增长 申请人的原纤维生长模型预测了稳定化， 在开发的特定时间段不稳定。 他们 假设这一过程涉及时间和空间的变化， 与线段曲面相关联的组件。 他们认为， 数据暗示了原纤维相关的蛋白聚糖和胶原。 在这 应用，他们将研究从预成型纤维的生长 肌腱和角膜这两种截然不同的组织中的中间物。 具体来说，他们将在和 在纤维快速生长期之后。 他们还将确定是否有一个 候选大分子之间存在相关性， 在纤维生长的特定阶段的表达/相互作用， 形态学、生物化学和分子遗传学方法。 作为候选人 被证实，它们在纤维生长的调节作用将是 考察 通过核心蛋白聚糖和纤维调节蛋白的调节将被研究 最初，申请人的数据表明在治疗期间核心蛋白聚糖的减少。 预测的不稳定时期，以及纤维调节蛋白在 基质稳定期。 这些的时间表达 候选分子在发育过程中会发生改变。 录病毒 将制备构建体以减少（反义或显性阴性），或 延长推定的调节分子的表达。 其影响将会 在体外使用胶原凝胶模型系统进行分析， 被感染的细胞 对肌腱原位发育的影响也将在 分析了 有人建议，了解的机制， 调节原纤维的形成、生长、基质组装和 组织特异性结构将导致对发育的理解， 生长，修复和病理学，以及遗传的操纵 紊乱

DESCRIPTION (Adapted from the Applicant's Abstract): Collagen stabilizes the structure of most organs. The applicants have demonstrated that fibrils are initially assembled as discrete fibril segments. These segments are incorporated into discontinuous fibers within developing extracellular matrices. As development proceeds, a regulated maturation of segments occurs. This involves the transformation of intermediates (segments) within the immature tissue into longer and, in most tissues, larger diameter fibrils (tendon); into longer fibrils with no change in diameter (cornea); or perhaps to persistence of segments (rapid remodeling). Relative to this application, it is hypothesized that segments undergo a post-depositional fusion, followed by molecular rearrangements that give rise to longer fibrils of the mature tissue. This hypothesis predicts changes in segment structure as fibrillogenesis proceeds from assembly of segments to fibril growth. The applicants' model of fibril growth predicts a stabilization and destabilization of segments at specific times in development. They hypothesize that this process involves temporal and spatial changes in components associated with the segment surface. They suggest that their data implicates the fibril-associated proteoglycans and collagens. In this application, they will study the growth of fibrils from preformed intermediates in two contrasting tissues, the tendon and cornea. Specifically, they will characterize the structure of segments during and after the period of rapid fibril growth. They also will determine whether a correlation exists between candidate macromolecules and expression/interaction at specific stages of fibril growth using morphological, biochemical and molecular genetic approaches. As candidates are substantiated, their roles in the regulation of fibril growth will be examined. Regulation via decorin and fibromodulin will be studied initially; the applicants' data indicating a decrease in decorin during the predicted period of destabilization, and an increase in fibromodulin during the period of matrix stabilization. The temporal expression of these candidate molecules will be altered during development. Retroviral constructs will be prepared to reduce (antisense or dominant-negative), or prolong expression of the putative regulatory molecules. The effects will be analyzed, in vitro, using a collagen gel model system populated by infected cells. The effects on tendon development in situ also will be analyzed. It is suggested that an understanding of the mechanisms regulating fibril formation, growth, matrix assembly and the development of tissue-specific architecture will lead to the understanding of development, growth, repair and pathobiology, as well as manipulations of inherited disorders.