Mechanisms Underlying Hormonal Regulation of Fracture Repair

本计划项目（PP）的总体目标是确定骨折修复调控的潜在机制，期望将研究的小鼠模型中获得的知识转化为退伍军人和军事人员骨折修复的新疗法。每个项目都将重点关注我们在初步实验中确定的对治疗过程至关重要的机制。项目 1将探讨胰岛素样生长因子-I（IGF-I）在协调软骨细胞，成骨细胞和破骨细胞之间的沟通在骨折愈合的顺序过程中的作用，首先在这些不同细胞中寻找特定的IGF-I及其受体的缺失，以确定这种缺失是否以及如何改变骨折愈合，然后检查可能是这些细胞之间沟通的信号通路。 细胞在愈合过程中。项目2将研究钙敏感受体（CaSR）在不同骨骼细胞中的作用，使用与项目1相同的方法，研究软骨细胞，成骨细胞和破骨细胞中CaSR的组织特异性缺失对骨折修复的影响。项目3将探讨G蛋白和wnt信号在介导甲状旁腺激素（PTH）促进细胞增殖的能力中的作用。 骨折修复将检查小鼠模型（其中抑制性G蛋白（Gi）本身被百日咳毒素的过表达抑制，并且wnt抑制剂sFRP 4以骨细胞特异性方式缺失）对骨折愈合本身和PTH促进骨折愈合的能力的影响。骨芯的主要重点是通过高强度骨密度提供愈合骨折的结构和力学分析。 所有三个计划项目（PP）的分辨率显微计算机断层扫描、组织形态测定、FTIR、微压痕和四点弯曲。此外，该中心还在开发评估微血管系统的方法，这对骨外的许多项目都很有用，但这也将为骨折修复的分析提供一种新的方法。Bikle博士将担任PI，Nissenson博士将担任PP的副PI， 在比克尔医生不在的时候担任私家侦探执行委员会将由3名项目PI和核心总监张博士组成。他们都是内分泌研究股的成员，共用该股的空间和设备。每个研究小组的每周实验室会议和ERU所有成员的每周战略会议将确保参与者之间的沟通。由当地骨生物学专家沿着以及我们的外部合作者组成的咨询委员会将每年对每个项目和整个PP进行外部审查。

The overall objective of this Program Project (PP) is to determine the mechanisms underlying the regulation of bone fracture repair with the expectation that the knowledge gained in the mouse models to be studied will be translated into new therapies for fracture repair in Veterans and Military Personnel. Each project will focus on a mechanism(s) that we have identified in preliminary experiments to be central for the healing process. Project 1 will explore the role of insulin-like growth factor-I (IGF-I) in coordinating the communication between chondrocytes, osteoblasts, and osteoclasts during the sequential process of fracture healing, looking first at specific deletions of IGF-I and its receptor in these different cells to determine if and how such deletions alter fracture healing, then examining the signaling pathways that may underlie the communication between these cells during the healing process. Project 2 will examine the role of the calcium sensing receptor (CaSR) in the different skeletal cells, using much of the same approach as in project 1 examining tissue specific deletions of CaSR in chondrocytes, osteoblasts, and osteoclasts for their impact on fracture repair. Project 3 will explore the role of G proteins and wnt signaling in mediating the ability of parathyroid hormone (PTH) to facilitate fracture repair. Mouse models in which the inhibitory G protein (Gi) is itself inhibited by overexpression of pertussis toxin, and the wnt inhibitor sFRP4 is deleted in a bone cell specific fashion will be examined for their impact on fracture healing per se, and on the ability of PTH to promote fracture healing. The Bone Core will have a primary focus on providing the structural and mechanical analyses of the healing fractures by high resolution micro computed tomography, histomorphometry, FTIR, micro indentation, and four point bending for all three Program Projects (PP). Moreover, the Core is also developing methods to evaluate the micro vasculature, useful for a number of projects outside of bone, but that will also provide a new approach to the analysis of bone fracture repair. Dr. Bikle will be the PI, and Dr. Nissenson will be the Associate PI of the PP, acting as PI in Dr. Bikle's absence. The executive committee will be comprised of the 3 PIs of the projects plus the Core Director, Dr. Chang. All are members of the Endocrine Research Unit (ERU) sharing space and equipment in that Unit. Weekly laboratory meetings by each research group and weekly strategy meetings with all members of the ERU will ensure ready communication among all participants of the PP. An Advisory Committee consisting of local experts in bone biology along with our outside collaborators will provide external review of each project and the PP overall on an annual basis.