Runx1 Control of Bone Resorption during Fracture Repair

Runx1 骨折修复过程中骨吸收的控制

基本信息

批准号：
9071289
负责人：
HICHAM M DRISSI
金额：
$ 33.89万
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：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9071289
关键词：
Apoptosis Bone Marrow Bone Regeneration Bone Resorption Bone callus Bone remodeling Cell Differentiation process Cells Dendritic Cells Development Disease Elements Event FOS gene Flow Cytometry Fracture Fracture Healing Gene Expression Gene Fusion Genes Healed Histologic Homeostasis ITGAM gene Image Analysis In Vitro Incidence Infection Knock-out Lead LoxP-flanked allele MMP9 gene Mediating Molecular Mus Myelogenous Names New Agents Osteoclasts Osteolysis Osteoporosis Phenotype Population Process Prosthesis Proteins RNA Repression Role Signal Transduction Site Small Interfering RNA Staging Stem cells Subfamily lentivirinae TNFSF11 gene Tamoxifen Time Transcription Repressor/Corepressor Transgenic Mice Viral Wild Type Mouse bone mass cathepsin K differential expression effective therapy gain of function gene repression genome-wide healing in vivo inhibitor/antagonist insight laser capture microdissection loss of function macrophage monocyte novel osteoclastogenesis overexpression phenotypic biomarker precursor cell progenitor public health relevance repaired research study skeletal skeletal regeneration substantia spongiosa transcription factor

项目摘要

DESCRIPTION (provided by applicant): We generated preliminary evidence showing that the number of osteoclasts in the fracture calluses of mice haploinsufficient for Runx1 is increased compared to wild type littermates. Furthermore, we found that targeted deletion of Runx1 in osteoclast precursors led to 25-30% decrease in trabecular bone mass and a 40-50% increase in bone resorption. Finally, we determined that Runx1 inhibits the expression of osteoclast specific genes in vitro. Thus, we hypothesized that Runx1 inhibits myeloid precursor cell differentiation into mature osteoclasts and in this way alters skeletal homeostasis and repair. We propose to: 1. Evaluate the role of Runx1 in regulating osteoclasts during bone remodeling and fracture repair. (Aim 1). We propose to determine whether: (i) Runx1 is a transcriptional repressor of osteoclast differentiation and function in vivo and (ii) if conditional deletion of Rux1 in precursors but not mature osteoclasts will impair fracture healing. 2. Define the mechanisms underlying Runx1-mediated inhibition of osteoclastogenesis. (Aim 2). We propose to determine whether (i) Runx1 is critical for early but not late osteoclast differentiation; (ii) examine if Rux1-mediated inhibition of osteoclastogenesis depends on inhibition of RANK-signaling; (iii) Runx1 alters osteoclast precursor lineage commitment and differentiation by regulating critical genes; (iv) Runx1 regulates myeloid precursor commitment towards various lineage fates. Our proposed experiments will provide a novel and integrated mechanistic insight into the transcriptional repression of osteoclast differentiation during skeletal regeneration and repair.

描述（由申请人提供）：我们产生了初步证据，表明与野生型乱货物相比，小鼠骨折call骨中的破骨细胞数量增加了。此外，我们发现在破骨细胞前体中靶向缺失Runx1导致小梁骨骼量下降25-30％，骨吸收增加了40-50％。最后，我们确定RUNX1在体外抑制破骨细胞特异性基因的表达。因此，我们假设RUNX1抑制髓样前体细胞分化为成熟的破骨细胞，以此方式改变了骨骼稳态和修复。我们建议：1。评估Runx1在调节骨重塑和断裂修复过程中调节破骨细胞中的作用。（目标1）。我们建议确定：（i）runx1是否是体内破骨细胞分化和功能的转录阻遏物，并且（ii）如果在前体中有条件的RUX1缺失，但不成熟的骨细胞会损害骨折愈合。 2。定义Runx1介导的抑制破骨细胞发生的机制。（目标2）。我们建议确定（i）runx1对于早期但不是晚期破骨细胞分化至关重要。（ii）检查RUX1介导的骨质发生抑制是否取决于降级信号的抑制作用；（iii）Runx1通过调节关键基因来改变破骨细胞前体的谱系谱系承诺和分化；（iv）RUNX1调节髓样前体对各种谱系命运的承诺。我们提出的实验将为骨骼再生和修复过程中破骨细胞分化的转录抑制提供新颖而综合的机械洞察力。