NG2/CSPG4 in Mandibular Endochondral Fracture Healing

NG2/CSPG4 在下颌软骨内骨折愈合中的应用

• 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
• 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

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.

项目摘要/摘要 该申请代表旨在为指导，职业发展和支持的培训计划 作为临床医生的申请人，试图将研究从台式机转移到颅面的床边 和口腔科学。培训计划包括实验室实验以及专业和职业 发展机会，该计划得到了杰出的地方和机构资源的支持 可在UIC上找到。拟议的研究将解决颅面面临的重要未满足的临床需求 创伤。下颌骨是最强，最大的面部骨头，但有很高的发病率 下颌骨折。与固定骨折相比，不稳定的下颌骨骨折表现出延迟的愈合，并且 他们的康复涉及软骨细胞到骨细胞的发育途径，该途径尚未完全理解。 了解控制断裂分辨率的特定分子途径对于改善裂缝很重要 临床结果和新疗法的发展。这项研究的重点是跨膜 蛋白聚糖，NG2/CSPG4。该分子与下颌的机械响应有关 颞下颌关节中的软骨细胞和骨关节炎的进展，但尚未研究 在内软骨骨折愈合的背景下。该提案中的研究计划利用了临床前鼠 下颌骨骨折愈合的模型，以及转基因敲除动物模型 定义NG2/CSPG4在成功的细胞分化级联中的作用 断裂愈伤组织的矿化。拟议的研究计划将检验机械的中心假设 依赖于加载的NG2/CSPG4信号传导调节骨软骨祖细胞的分化 下颌骨折中的软骨骨化。长期，我们的目标是了解细胞如何制造 关于其骨骼再生期间命运的决定。 AIM 1将评估NG2/CSPG4在能力中的作用 骨软骨祖细胞分化为软骨。 AIM 2将重点介绍NG2/CSPG4在 软骨细胞经历矿化的能力。从该项目产生的数据将解决 围绕下颌骨折愈合和骨骼生物学的知识的重要差距，更广泛， 可以确定一个新的治疗靶点来进行临床干预。