Role of the first secreted tyrosine kinase in bone development, homeostasis, and repair.

 描述（由申请人提供）：细胞外基质（ECM）是分泌骨架的发育-转录控制的高度动态组分。虽然在骨骼发育过程中ECM成分的转录控制被深入研究，但ECM及其调节剂的后组分相对知之甚少。我们已经确定了一类新的调节分泌蛋白，第一个已知的分泌蛋白酪氨酸激酶（VLK）是必不可少的正常软骨内骨形成。我们发现VLK磷酸化广泛的分泌蛋白质，在骨骼发育和骨量维持中发挥作用。VLK还磷酸化在骨ECM分泌中具有特定作用的常驻ER蛋白，因此不仅可以直接修饰分泌蛋白，而且可以通过控制软骨内骨化和骨折软骨内骨化细胞期间的β介导的磷酸化中的分泌过程间接修饰分泌蛋白。在本提案中，我们计划建立VLK的功能作用-修复。我们将使用体外和体内方法相结合，以确定在endochondrial细胞VLK的基板，确定VLK介导的磷酸化在体内的空间和时间模式，建立VLK如何修改软骨细胞分化和endochondrial骨化，并检查特定分泌底物的VLK磷酸化的功能。这些研究将确定一个新的机制，为骨ECM功能的调节，提供一个新的方法来治疗调节骨骼发育，稳态和修复。

 DESCRIPTION (provided by applicant): The extracellular matrix (ECM) is a highly dynamic component of the developing -transcriptional control of the secreted skeleton. While the transcriptional control of ECM composition during skeletal development is intensively studied, the post-- components of the ECM and its regulators are relatively poorly understood. We have identified a novel class of regulator of secreted proteins, the first known secreted protein tyrosine kinase (VLK) that is essential for normal endochondral bone formation. We find that VLK phosphorylates a wide range of secreted proteins with established roles in skeletal development and maintenance of bone mass. VLK also phosphorylates resident ER proteins with specific roles in bone ECM secretion, and thus may modify secreted proteins not only directly, but also indirectly through control of the secretion process in -mediated phosphorylations both during endochondral ossification and during fracture endochondral cells. In this proposal, we plan to establish the functional role of VLK- repair. We will use a combination of in vitro and in vivo approaches to identify substrates for VLK in endochondral cells, identify spatial and temporal patterns of VLK mediated phosphorylations in vivo, establish how VLK modifies chondrocyte differentiation and endochondral ossification, and examine the function of VLK phosphorylation of specific secreted substrates. These studies will define a new mechanism for the regulation of ECM function in bone, providing a new approach to the therapeutic modulation of skeletal development, homeostasis, and repair.