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Rspondin-Lgr Axis in Bone Regeneration

骨再生中的 Rspondin-Lgr 轴

基本信息

批准号：
10469469
负责人：
Kurt David Hankenson
金额：
$ 37.94万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469469
关键词：
Address Adult Attenuated BMP2 gene Binding Bone Injury Bone Regeneration Bone callus Calvaria Cell Lineage Cells Chondrocytes Clinical Data Defect Development Embryo Family Family member Fracture GPR4 gene Genes Goals Hand Histology In Vitro Incidence Individual Injury Knockout Mice Lead Leucine-Rich Repeat Ligands Limb Development Limb structure LoxP-flanked allele Mechanics Mesenchymal Mesenchymal Stem Cells Mesenchyme Minerals Modeling Molecular Molecular Analysis Mus Osteoblasts Osteogenesis Pathway interactions Periosteal Cell Periosteum Play Positioning Attribute Process Property Proteins Public Health Publishing Receptor Signaling Recombinants Regulation Reporter Research Role Signal Transduction Site Skeletal Development Testing Therapeutic Uses Time WNT Signaling Pathway base bone bone fracture repair bone healing bone repair craniofacial healing in vivo injured long bone mRNA Expression microCT mouse model novel novel strategies novel therapeutics osteoblast differentiation osteochondral tissue osteogenic osteoprogenitor cell prevent progenitor protein function receptor regenerative therapy response response to injury skeletal stem stem cells tissue regeneration

项目摘要

There is an urgent clinical need to develop new therapeutics to promote bone regeneration. A critical aspect of the bone healing process begins with the expansion of periosteal progenitors that occurs immediately after injury and then the differentiation of these progenitors to bone forming osteoblasts and chondrocytes, yet mechanisms that control skeletal progenitor/stem cell activation, expansion, and differentiation in response to injury are poorly described. Our project will study the role of the R-spondin (ligand) – Lgr (receptor) signaling axis in regulating these progenitors and bone regeneration. R-spondins (roof plate specific spondin) are a family of four secreted matricellular proteins (Rspo1-4) that bind to Leucine-rich repeat-containing G-protein coupled receptors 4/5/6 (Lgrs). Rspo-Lgr interaction potentiate canonical Wnt pathway by preventing the turnover of Wnt Frizzled receptors, and hence determines canonical Wnt signaling levels. While canonical Wnt signaling is known to play an important role in bone regeneration, very little research has explored positive modulators of Wnt signaling. In particular, the requirement of Rspo-Lgr in the context of fracture healing has never been examined due to lack of appropriate models. Our primary goal is to define the requirement of Rspo2/3 and Lgr6 in mesenchymal progenitors in response to bone injury. We have defined three specific aims to address this goal. In Aim1, we will use single and compound Rspo2 and Rspo3 floxed mice crossed with an alphaSMACreERT2 mouse to disrupt the Rspo2/3 genes in mesenchymal progenitors at the time of fracture. Bone healing will be assessed using microCT, histology, molecular analysis, and mechanical testing. Alterations in canonical Wnt signaling and osteogenic potential of Rspo2/3 deficient progenitors will be assessed. In Aim 2, Lgr6 knockout mice will be investigated for their bone healing properties using parameters similar to Aim 1. In Aim 3, Rspo2 will be delivered to bone injury sites and the impact on BMP and Wnt signaling, progenitor activation and differentiation, and bone healing assessed. Completion of this project will identify the requirement of Rspo2/3-Lgr6 interaction in fracture healing and will provide new therapeutic directions for enhancing bone healing.

临床迫切需要开发新的治疗方法来促进骨再生。一个