NG2/CSPG4 in Mandibular Endochondral Fracture Healing

NG2/CSPG4 在下颌软骨内骨折愈合中的应用

基本信息

批准号：
10752209
负责人：
Jonathan Matthew Banks
金额：
$ 5.35万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2029-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752209
关键词：
Address Alkaline Phosphatase Animal Model Biological Markers Biology Bone Regeneration Bone callus CSPG4 gene Cartilage Cell Differentiation process Cells Chondrocytes Clinical Collagen Type VI Data Decision Making Degenerative polyarthritis Development Epiphysial cartilage Exhibits Fracture Goals Immunohistochemistry Impaired healing Impairment In Vitro Incidence Institution Intervention Joint structure of suture of skull Knockout Mice Knowledge Ligands Limb structure Link MAPK3 gene Mandible Mandibular Fractures Mechanics Membrane Mentors Molecular Neck Oral Osteoblasts Osteotomy Outcome Outcome Study Pain Pathway interactions Patient-Focused Outcomes Periosteum Physiologic Ossification Postoperative Period Proteoglycan Quality of life Regulation Research Resolution Resources Role Science Scientist Signal Transduction Skeletal system Temporomandibular Joint Testing Time Tissues Training Transgenic Organisms Trauma Western Blotting Work bone bone fracture repair calcification career development cartilage cell cell injury cell type condylar cartilage craniofacial design face bone structure healing improved in vivo intramembranous bone formation knockout animal laboratory experiment mechanical load mineralization mouse model new therapeutic target novel therapeutics osteochondral tissue osteogenic osteoprogenitor cell pre-clinical receptor response response to injury stem cells

项目摘要

PROJECT SUMMARY/ABSTRACT This application represents a training plan designed to provide mentoring, career development, and support to the applicant as a clinician-scientist seeking to move research from the benchtop to the bedside in craniofacial and oral sciences. The training plan encompasses laboratory experimentation and professional and career development opportunities, and the plan is supported by the outstanding local and institutional resources available at UIC. The proposed research will address an important unmet clinical need facing craniofacial trauma. While the mandible is the strongest and largest facial bone, there is a high level of incidence for mandibular fractures. Unstable mandibular fractures exhibit delayed healing compared to fixed fractures, and their healing involves a chondrocyte-to-osteoblast developmental pathway that is not yet fully understood. Understanding the specific molecular pathways that control fracture resolution is important for improving clinical outcomes and the development of new therapeutics. The focus of this study is on a transmembrane proteoglycan, NG2/CSPG4. This molecule has been implicated in the mechanical response of mandibular chondrocytes in the temporomandibular joint and the progression of osteoarthritis, but it has not been studied in the context of endochondral fracture healing. The research plan in this proposal utilizes a preclinical murine model of endochondral fracture healing in the mandible, together with transgenic knockout animal models, to define the role of NG2/CSPG4 in the cell differentiation cascade that is required for the successful mineralization of a fracture callus. The proposed research plan will test the central hypothesis that mechanical loading-dependent NG2/CSPG4 signaling regulates the differentiation of osteochondral progenitor cells during endochondral ossification in mandibular fractures. Long-term, our goal is to understand how cells make decisions about their fate during bone regeneration. Aim 1 will evaluate the role of NG2/CSPG4 in the ability of osteochondral progenitor cells to differentiate into cartilage. Aim 2 will focus on the role of NG2/CSPG4 in the ability of cartilage cells to undergo mineralization. Together, the data generated from this project will address an important gap in knowledge surrounding mandibular fracture healing and bone biology more broadly and may identify a new therapeutic target for clinical intervention.

项目概要/摘要此应用程序代表一项培训计划，旨在为以下人员提供指导、职业发展和支持：申请人作为一名临床医生科学家，寻求将颅面部研究从实验室转移到床边和口腔科学。培训计划包括实验室实验以及专业和职业发展机遇，且该计划得到优秀的地方和机构资源的支持可在 UIC 获取。拟议的研究将解决颅面部面临的重要的未满足的临床需求创伤。虽然下颌骨是面部最坚固、最大的骨骼，但下颌骨的发病率很高。下颌骨骨折。与固定骨折相比，不稳定的下颌骨折表现出愈合延迟，并且它们的愈合涉及软骨细胞到成骨细胞的发育途径，但目前尚未完全了解。了解控制骨折分辨率的特定分子途径对于提高骨折愈合率非常重要临床结果和新疗法的开发。本研究的重点是跨膜蛋白多糖，NG2/CSPG4。该分子与下颌的机械反应有关颞下颌关节软骨细胞与骨关节炎的进展有关，但尚未研究在软骨内骨折愈合的背景下。本提案中的研究计划利用临床前小鼠下颌骨软骨内骨折愈合模型与转基因敲除动物模型一起，定义 NG2/CSPG4 在成功分化所需的细胞分化级联中的作用骨折愈伤组织的矿化。拟议的研究计划将检验机械的中心假设负载依赖性 NG2/CSPG4 信号调节骨软骨祖细胞的分化下颌骨骨折中的软骨内骨化。从长远来看，我们的目标是了解细胞如何制造在骨骼再生过程中决定它们的命运。目标 1 将评估 NG2/CSPG4 在以下能力中的作用：骨软骨祖细胞分化成软骨。目标 2 将重点关注 NG2/CSPG4 在软骨细胞进行矿化的能力。该项目生成的数据将共同解决更广泛地围绕下颌骨折愈合和骨生物学的知识存在重要差距可能会为临床干预确定新的治疗靶点。