Mechanisms Underlying Hormonal Regulation of Fracture Repair

骨折修复的激素调节机制

• 批准号: 8413380
• 负责人: DANIEL David BIKLE
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413380
• 关键词: Advisory Committees; Affect; Animal Model; Area; Arterial Fatty Streak; Biology; Blood Vessels; Bone Development; Bone callus; Bone remodeling; Businesses; Calcium; Calcium-Sensing Receptors; Cartilage; Cells; Chondrocytes; Clinical; Communication; Degenerative polyarthritis; Development; Diabetes Mellitus; Endocrine; Ensure; Environment; Equipment; Fourier Transform; Fracture; Fracture Healing; Funding; GTP-Binding Proteins; Glues; Healed; Health; Heterotopic Ossification; Hormones; Human Resources; Individual; Inhibitory G-Protein Gi; Institution; Insulin-Like Growth Factor I; Kidney Calculi; Knowledge; Laboratories; Malnutrition; Mechanics; Mediating; Medical; Methods; Military Personnel; Modeling; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid gland; Participant; Pathway interactions; Pertussis Toxin; Population; Positioning Attribute; Process; Regulation; Research; Research Personnel; Resolution; Resources; Role; San Francisco; Services; Signal Pathway; Signal Transduction; Skeletal system; Spectrum Analysis; Stroke; Structure; Sum; Techniques; Tissues; Translating; Traumatic Brain Injury; Veterans; Vitamin D; Work; X-Ray Computed Tomography; base; bone; bone cell; bone imaging; calcification; computerized data processing; expectation; healing; hormone regulation; inhibitor/antagonist; interest; meetings; member; mouse model; new technology; novel strategies; overexpression; parathyroid hormone-related protein; programs; receptor; repaired; research study; skeletal

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.

该计划项目（PP）的总体目标是确定骨折修复调节的潜在机制，期望在待研究的小鼠模型中获得的知识将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治疗过程核心机制。项目 1 将探讨胰岛素样生长因子-I (IGF-I) 在协调骨折愈合过程中软骨细胞、成骨细胞和破骨细胞之间的通讯中的作用，首先观察 IGF-I 及其受体的特定缺失。这些不同的细胞以确定这些缺失是否以及如何改变骨折愈合，然后检查可能构成这些细胞之间通讯基础的信号传导途径 愈合过程中的细胞。项目 2 将检查钙敏感受体 (CaSR) 在不同骨骼细胞中的作用，使用与项目 1 大致相同的方法，检查软骨细胞、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 将探索 G 蛋白和 Wnt 信号传导在介导甲状旁腺激素 (PTH) 促进功能的能力中的作用。 骨折修复。在小鼠模型中，抑制性 G 蛋白 (Gi) 本身受到百日咳毒素过度表达的抑制，并且以骨细胞特异性方式删除 wnt 抑制剂 sFRP4，将检查它们对骨折愈合本身的影响，以及对骨折愈合能力的影响。 PTH促进骨折愈合。 Bone Core 的主要重点是通过高强度骨折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、组织形态测量、FTIR、显微压痕和四点弯曲。此外，该核心还在开发评估微脉管系统的方法，这对于骨骼以外的许多项目很有用，但这也将为分析骨折修复提供一种新方法。 Bikle 博士将担任 PP 的 PI，Nissenson 博士将担任 PP 的副 PI， 在 Bikle 博士不在时担任 PI。执行委员会将由项目的 3 名 PI 以及核心总监张博士组成。他们都是内分泌研究室 (ERU) 的成员，共享该室的空间和设备。每个研究小组每周举行的实验室会议以及与 ERU 所有成员举行的每周战略会议将确保 PP 的所有参与者之间随时进行沟通。由当地骨生物学专家和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。