Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix

项目总结 几种分泌型ECM蛋白的突变，包括ADAMTSL2，ADAMTS10，ADAMTS17，LTBP2，LTBP3， 和纤维蛋白-1(FBN1)，可引起肢端发育不良，如生殖器发育不良或Weill-Marchesani 综合症。所有肢端发育不良都有相同的肌肉骨骼表现，包括身材矮小、关节 肌挛缩和肌肉过度发达，这表明肢端发育不良中突变的蛋白质在 肌肉骨骼组织的细胞外基质，作为肢端发育不良蛋白复合体的一部分或作为肢端发育不良蛋白复合体的一部分 调节肌肉骨骼发育和动态平衡的分子途径。虽然有些函数用于 在肢端发育不良中突变的个别蛋白质已经出现，关于 这些蛋白质之间的直接相互作用和相互关系。例如，重组ADAMTSL2和 ADAMTS10可与纤维蛋白-1结合。然而，目前尚不清楚这两种蛋白质是否能够相互结合，或者是否占据了 与原纤维蛋白-1上的位置相同。在肢端发育不良中，任何一种蛋白质是如何妥协的也是未知的， 包括ADAMTSL2和ADAMTS10，都参与了骨骼肌的形成和动态平衡。在这里，我们 建议测试ADAMTS10和ADAMTSL2相互作用的假设，或者直接或 通过纤维蛋白-1微纤维支架，它们在调节骨骼肌形成方面相互合作。在……里面 具体目标1，我们将分析ADAMTS10在骨骼肌分化中的作用，并研究是否 ADAMTS10与ADAMTSL2合作。在特定目标2中，我们将调查ADAMTSL2和ADAMTS10 可以直接相互作用，并在与纤维蛋白-1相互作用时确定它们的空间关系。有了预期的 结果我们将开始定义肢端发育不良复合体的成分的功能作用 然后可以通过包括由突变的基因编码的附加成分来扩展 发育不良。这些见解将有助于了解蛋白质是如何影响肢端发育不良的 共同管理骨骼肌和肌肉骨骼组织的发育和动态平衡。

PROJECT SUMMARY Mutations in several secreted ECM proteins, including ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, LTBP3, and fibrillin-1 (FBN1), can cause acromelic dysplasias, such as geleophysic dysplasia or Weill-Marchesani syndrome. All acromelic dysplasias share identical musculoskeletal presentations, including short stature, joint contractures and hypermuscularity, which suggests that proteins mutated in acromelic dysplasias cooperate in the ECM of musculoskeletal tissues, either as part of an acromelic dysplasia protein complex or as part of a molecular pathway that regulates musculoskeletal development and homeostasis. While some functions for the individual proteins that are mutated in acromelic dysplasias have emerged, there is very little information about the direct interaction and interrelationship between these proteins. For example, recombinant ADAMTSL2 and ADAMTS10 can bind to fibrillin-1. However, it is unknown, if both proteins can bind to each other or if the occupy the same site on fibrillin-1. It is also not known how any of the proteins compromised in acromelic dysplasia, including ADAMTSL2 and ADAMTS10, are involved in skeletal muscle formation and homeostasis. Here, we propose to test the hypothesis that ADAMTS10 and ADAMTSL2 interact with each other, either directly or through the fibrillin-1 microfibril scaffold, and that they cooperate in regulating skeletal muscle formation. In specific aim 1, we will analyze the role of ADAMTS10 in skeletal muscle differentiation and investigate if ADAMTS10 cooperates with ADAMTSL2. In specific aim 2, we will investigate if ADAMTSL2 and ADAMTS10 can interact directly and determine their spatial relationship when interacting with fibrillin-1. With the expected results we will begin to define the functional role of the components of the acromelic dysplasia complex which can then be extended by including additional components encoded by the genes mutated in acromelic dysplasias. These insights will contribute to the quest to understand how proteins affected in acromelic dysplasia work together to govern skeletal muscle and musculoskeletal tissue development and homeostasis.