REGULATED ASSEMBLY OF TENDON EXTRACELLULAR MATRIX

描述（由申请人提供）：本申请的重点是 确定肌腱细胞外基质组装的机制， 初始纤维组装的独立调节以及 长度和直径。肌腱特异性基质的组装是多步骤的 过程我们的模型是，胶原纤维最初组装为离散的， 原纤维中间体，其在发育中被并入纤维中， 矩阵随后是纤维的调节生长和成熟， 这些预成型的中间体。这涉及到组装，以形成更长的（线性 生长）和较大直径（侧向生长）的原纤维。的说明， 调节这些步骤的机制对于理解正常的 肌腱发育本申请的具体目的是：（1）定义 与纤维发生相关的纤维亚群，并分析 在肌腱发育过程中原纤维长度的变化，（2）表征的作用 异型I/III型胶原蛋白相互作用的调节组装 （3）阐明核心蛋白聚糖、光蛋白聚糖和 纤调蛋白在调节肌腱原纤维形成中的特定步骤中的作用;以及 (4)确定XIV型胶原在原纤维生长调节中的作用。我们 将利用缺乏III型胶原，XIV型胶原， 核心蛋白聚糖、纤调蛋白或光蛋白聚糖， 生物化学和免疫化学方法。一种假设是， 纤维状胶原蛋白异型相互作用是调节 胶原最初组装成纤维中间体。此外，本发明还提供了一种方法， 富含亮氨酸的重复蛋白在肌腱发育的不同阶段起作用， 调节纤维形成的特定步骤。不同的表达模式， 结合位点和结合亲和力介导这些作用。我们还假设 XIV型胶原蛋白参与调节转化为 通过线性增长控制进展。这些研究将确定 调节肌腱特异性基质组装步骤的机制 发展和导致潜在的操纵过程中的增长，损伤和 修复，以及对遗传性疾病的理解。

DESCRIPTION (provided by applicant): The focus of this application is to determine the mechanisms of tendon extracellular matrix assembly that allow for the independent regulation of initial fibril assembly as well as growth in length and diameter. Assembly of the tendon-specific matrix is a multistep process. Our model is that collagen fibrils are initially assembled as discrete fibril intermediates that are incorporated into fibers within the developing matrix. This is followed by a regulated growth and maturation of fibrils from these preformed intermediates. This involves assembly to form longer (linear growth) and larger diameter (lateral growth) fibrils. The elucidation of the mechanisms regulating these steps is essential to an understanding of normal tendon development. The Specific Aims of this application are to: (1) define the fibril sub-populations associated with fibrillogenesis and analyze the changes in fibril length during tendon development, (2) characterize the roles of heterotypic type I/III collagen interactions in the regulation of assembly of tendon fibril intermediates; (3) elucidate the roles of decorin, lumican and fibromodulin in the regulation of specific steps in tendon fibrillogenesis; and (4) determine the roles of type XIV collagen in regulation of fibril growth. We will utilize transgenic mice deficient in type III collagen, type XIV collagen, decorin, fibromodulin or lumican with structural, morphometric, molecular, biochemical and immunochemical approaches. One hypothesis is that the heterotypic interaction of fibrillar collagens is a major mechanism regulating the initial assembly of collagen into fibril intermediates. In addition, leucine-rich repeat proteins act at different stages in tendon development to regulate specific steps in fibrillogenesis. Different expression patterns, binding sites and binding affinities mediate these effects. We also hypothesize that type XIV collagen is involved in regulating the transition into and controlled progression through linear growth. These studies will define the mechanisms regulating the steps in tendon-specific matrix assembly during development and lead to potential manipulations during growth, injury and repair, as well as to the understanding of inherited disorders.