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Hox Gene Regulation of Skeletal Repair

Hox 基因对骨骼修复的调控

基本信息

批准号：
10685496
负责人：
Katharine A. Hubert
金额：
$ 1.86万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685496
关键词：
Acute Adipocytes Adult Alleles Animal Experiments Animals Anterior Behavior Biological Biological Assay Bone Marrow Bone Matrix Bone callus Bone remodeling Cartilage Cell Culture Techniques Cell Differentiation process Cell Lineage Cells Chondrocytes Chondrogenesis Collagen Collection Control Animal Data Defect Development Developmental Process Embryonic Development Event Exhibits Fracture Gene Expression Gene Expression Regulation Genes Genetic Genetic Recombination Goals Growth Histocytochemistry Histology Homeobox Genes Homeostasis Injury Knowledge Label Laboratories Life Maintenance Measures Mediating Mesenchymal Mesenchymal Stem Cells Modeling Molecular Mus Natural regeneration Organ Osteoblasts Osteocytes Osteogenesis Pathway interactions Pattern Population Process Proliferating Radial Reporter Reporting Roentgen Rays Role Skeleton Small Interfering RNA Sorting Stromal Cells Testing Time Tomatoes Work bone bone cell bone fracture repair cartilage cell conditional mutant differential expression fibula gene function healing injury and repair insight loss of function microCT mouse model mutant osteogenic paralogous gene postnatal progenitor repaired response response to injury self-renewal single cell analysis single cell sequencing skeletal skeletal stem cell stem stem cell population stem cells tibia tool transcription factor transcriptome sequencing transcriptomics ulna

项目摘要

PROJECT SUMMARY/ABSTRACT Hox genes are a group of evolutionarily conserved transcription factors important for several developmental processes, including patterning of the anterior-posterior axis of the skeleton. The Hox11 paralogous gene group, which is expressed in the zeugopod region (radius/ulna and fibula/tibia), are necessary for proper patterning of the zeugopod. In the past few years, work from the Wellik laboratory has shown that these developmentally important Hox transcription factors remain expressed in the skeleton throughout life, specifically in progenitor-enriched mesenchymal stem cells (MSCs). Rigorous genetic lineage labeling from the lab demonstrated that these cells give rise to all three mesenchymal lineages, osteoblasts, chondrocytes and adipocytes, and exhibit life-long self-renewal, providing strong evidence that this population of cells are skeletal stem cells. A key question based on this information is whether Hox gene function is important in these stem cells throughout life. We recently reported that temporal deletion of Hox11 at adult stages results in defects in osteoblastogenesis, wherein differentiation is initiated, but osteoblasts and osteocytes fail to mature. Adult conditional loss of Hox11 function results in a progressively weakened bone matrix where collagen does not properly assemble in remodeling bone. In this study, I will use a temporally-controlled, conditional loss-of- function model to assess defects in response to fracture repair (Aim 1). Preliminary data shows that temporally-deleted, ROSACreERT2/+;Hoxa11eGFP/-;Hoxd11LoxP/LoxP mice are unable to repair after fracture. Additionally, preliminary data suggest that the populations of osteoblasts and chondrocytes appear to be in abnormal in mutants. Using Hoxa11CreERT2 to enact both deletion and lineage labeling, I can mark the cells that have undergone recombination for isolation and transcriptomic analyses (Hoxa11eGFP/CreERT2;Hoxd11LoxP/LoxP; ROSAtd-Tomato/+, Aim 2). Fracture injury induces an acute response in which stem/progenitor expansion and differentiation to both skeletal lineages is occurring simultaneously, providing an excellent model to isolate single cells and identify the pathways and targets Hox genes regulate in these processes. Preliminary data shows that a large proportion of GFP+ cells are available for collection from the fracture callus, making single cell sequencing not only possible, but a highly effective tool to investigate transcriptomic change in Hox- expressing and Hox-lineage cells. The overall goal of this project is to define Hox genetic function in fracture repair and to identify the molecular mechanisms by which Hox genes regulate skeletal behavior in this process.

项目总结/文摘