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.

项目摘要 几种分泌的ECM蛋白中的突变，包括ADAMTSL 2、ADAMTS 10、ADAMTS 17、LTBP 2、LTBP 3、 和BFN-1（FBN 1），可引起肢端发育不良，如胶状发育不良或Weill-Marchesani 综合征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、关节发育不良、 挛缩和肌肉发达，这表明在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。虽然一些函数 肢端发育不良中突变的个别蛋白质已经出现，但关于这方面的信息很少。 这些蛋白质之间的直接相互作用和相互关系。例如，重组ADAMTSL 2和 ADAMTS 10可以与Escherichin-1结合。然而，目前尚不清楚这两种蛋白质是否可以相互结合，或者是否占据了 也是同样的地点也不知道肢端发育不良中的任何蛋白质是如何受损的， 包括ADAMTSL 2和ADAMTS 10参与骨骼肌形成和体内平衡。这里我们 我建议测试假设ADAMTS 10和ADAMTSL 2相互作用，直接或 通过骨形成蛋白-1微纤维支架，并且它们在调节骨骼肌形成中合作。在 具体目标1，我们将分析ADAMTS 10在骨骼肌分化中的作用，并调查是否 ADAMTS 10与ADAMTSL 2配合使用。在具体目标2中，我们将研究ADAMTSL 2和ADAMTS 10 可以直接相互作用，并确定它们在与Repeat in-1相互作用时的空间关系。与预期 结果我们将开始确定肢端发育不良复合体成分的功能作用， 然后可以通过包括由肢端病中突变的基因编码的额外成分来扩展， 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 共同控制骨骼肌和肌肉骨骼组织的发育和体内平衡。