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.

项目总结/摘要 此应用程序代表一个培训计划，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科学家，寻求将颅面研究从台式转移到床边 口腔科学培训计划包括实验室实验和专业和职业 发展机会，该计划得到了优秀的地方和机构资源的支持 在UIC。拟议的研究将解决颅面神经外科面临的一个重要的未满足的临床需求。 外伤虽然下颌骨是最坚固和最大的面部骨骼，但 下颌骨骨折与固定骨折相比，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，但目前尚未完全了解。 了解控制裂缝分辨率的特定分子途径对于改善裂缝分辨率是重要的。 临床结果和新疗法的开发。这项研究的重点是跨膜 蛋白聚糖，NG 2/CSPG 4。这种分子与下颌骨的机械反应有关 软骨细胞在颞下颌关节和骨关节炎的进展，但还没有研究 in the context背景of endochondrialfracture内骨折healing愈合.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，以及转基因敲除动物模型， 确定NG 2/CSPG 4在细胞分化级联中的作用，这是成功的细胞分化所必需的。 骨折骨痂的矿化。拟议中的研究计划将检验中心假设， 负荷依赖性NG 2/CSPG 4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是如何 决定他们在骨再生过程中的命运。目的1将评估NG 2/CSPG 4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NG 2/CSPG 4在 软骨细胞进行矿化的能力。总之，从这个项目产生的数据将解决 更广泛地围绕下颌骨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。