Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix

软组织细胞外基质对骨骼生长的调节

• 批准号: 10320133
• 负责人: Dirk Hubmacher
• 金额: $ 0.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320133
• 关键词: ADAMTS; Affect; Binding; Complex; Contracture; Development; Disease; Dysplasia; Extracellular Matrix; Extracellular Matrix Proteins; FBN1; Genes; Growth; Homeostasis; Individual; Joints; LTBP2 gene; Microfibrils; Molecular; Musculoskeletal; Musculoskeletal Development; Mutate; Mutation; Pathway interactions; Proteins; Recombinants; Regulation; Role; Site; Skeletal Muscle; Symptoms; Testing; Tissues; Weill-Marchesani syndrome; Work; geleophysic dysplasia; insight; novel; novel therapeutic intervention; protein complex; scaffold; skeletal; skeletal muscle differentiation; skeletal muscle growth; soft tissue; spatial relationship

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.

项目概要 多种分泌型 ECM 蛋白发生突变，包括 ADAMTSL2、ADAMTS10、ADAMTS17、LTBP2、LTBP3、 和 fibrillin-1 (FBN1)，可引起肢端发育不良，例如凝胶发育不良或 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 挛缩和肌肉过多，这表明肢端发育不良中突变的蛋白质协同作用 肌肉骨骼组织的 ECM，作为肢端发育不良蛋白复合物的一部分或作为 调节肌肉骨骼发育和体内平衡的分子途径。虽然某些功能对于 肢端发育不良中突变的个别蛋白质已经出现，但有关的信息很少 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 可以与 fibrillin-1 结合。然而，尚不清楚这两种蛋白质是否可以相互结合，或者是否占据 fibrillin-1 上的相同位点。也不知道在肢端发育不良中任何蛋白质是如何受损的， 包括 ADAMTSL2 和 ADAMTS10，参与骨骼肌形成和体内平衡。在这里，我们 提议检验 ADAMTS10 和 ADAMTSL2 直接或直接相互作用的假设 通过 fibrillin-1 微纤维支架，它们协同调节骨骼肌的形成。在 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 ADMTSL2 配合。在具体目标 2 中，我们将研究 ADAMTSL2 和 ADAMTS10 是否 与fibrillin-1相互作用时可以直接相互作用并确定它们的空间关系。与预期的 结果我们将开始定义肢端发育不良复合体成分的功能作用 然后可以通过包含由顶体突变基因编码的附加组件来扩展 发育不良。这些见解将有助于了解蛋白质如何影响肢端发育不良 共同努力控制骨骼肌和肌肉骨骼组织的发育和体内平衡。