NG2/CSPG4 in Mandibular Endochondral Fracture Healing

项目摘要/摘要 此应用程序代表旨在提供指导、职业发展和支持的培训计划 申请人为临床医生兼科学家，寻求将研究从头面部的台面转移到床边 和口腔科学。培训计划包括实验室实验以及专业和职业生涯 发展机会，该计划得到当地和机构资源的支持 可在UIC获得。拟议的研究将解决颅面部面临的一个重要的未得到满足的临床需求。 精神创伤。虽然下颌骨是最强壮和最大的面部骨骼，但 下颌骨骨折。与固定性骨折相比，不稳定的下颌骨骨折愈合延迟。 它们的愈合涉及软骨细胞到成骨细胞的发育途径，目前还不完全清楚。 了解控制裂缝分辨率的特定分子途径对于提高裂缝分辨率很重要 临床结果和新疗法的开发。这项研究的重点是跨膜 蛋白多糖，NG2/CSPG4。该分子参与了下颌骨的机械反应。 颞下颌关节软骨细胞与骨关节炎的进展，但尚未被研究 在软骨内骨折愈合的背景下。这项建议中的研究计划利用了一只临床前小鼠 下颌骨软骨内骨折愈合模型和转基因基因敲除动物模型 明确NG2/CSPG4在成功的细胞分化级联反应中的作用 骨折骨痂的矿化。拟议的研究计划将检验机械的核心假设 负载依赖的NG2/CSPG4信号调节骨软骨前体细胞分化 下颌骨骨折的软骨内骨化。从长远来看，我们的目标是了解细胞是如何 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 骨软骨前体细胞分化为软骨。目标2将侧重于NG2/CSPG4在 软骨细胞的矿化能力。总而言之，该项目产生的数据将解决 关于下颌骨骨折愈合和更广泛的骨生物学知识的重要差距 可能为临床干预寻找新的治疗靶点。

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.