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Cell-Matrix Regulation of Fibrochondrocytes in TMJ OA

TMJ OA 中纤维软骨细胞的细胞基质调节

基本信息

批准号：
10209687
负责人：
David Andrew Reed
金额：
$ 43.36万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209687
关键词：
Address Affect Antigens Apoptosis Arthritis Attenuated Autophagocytosis Binding Biochemical Bioreactors Cartilage Cartilage Diseases Cell Death Cell physiology Cells Chondrocytes Clinical Collagen Type VI Cytoprotection Data Degenerative polyarthritis Disease Early Intervention Endocytosis Exposure to Extracellular Matrix FRAP1 gene Fibroblasts Flow Cytometry Functional disorder Goals Health Hip region structure Histology Human Immunohistochemistry Impairment In Vitro Inflammatory Injury Integrin Binding Joints Knockout Mice Knowledge Limb structure Link Maintenance Mandible Mechanical Stress Mechanics Mediating Modeling Molecular Monoclonal Antibodies Neurons Operative Surgical Procedures Outcome Pain Pathogenesis Pathology Pathway interactions Patients Population Process Proteoglycan Proteolysis Quality of life Regulation Replacement Arthroplasty Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Sirolimus Stress Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular Joint Dysfunction Syndrome Temporomandibular joint arthritis Temporomandibular joint osteoarthritis Testing Western Blotting Work base cartilage degradation cost design experimental study immunocytochemistry in vivo inhibitor/antagonist innovation joint injury joint mobilization mouse model neuron loss novel novel therapeutic intervention pre-clinical receptor response response to injury therapeutic target

项目摘要

ABSTRACT Cell-matrix regulation of fibrochondrocytes in TMJ OA Disorders of the temporomandibular joint (TMJ) affect between 3-7% of the population and osteoarthritis (OA) is the most common pathology associated with TMJ dysfunction. TMJ OA is a disease of cartilage degeneration and chondrocyte apoptosis. One of the key factors leading to chondrocyte apoptosis is the suppression of the cytoprotective process of autophagy. Autophagy is one of the earliest cellular responses to TMJ OA and has been shown to be a viable therapeutic target for attenuating the progression of cartilage degeneration. A major gap in knowledge is how mechanical and inflammatory stress leads to the eventual suppression of autophagy, apoptosis, and cartilage degeneration. To address this gap, my lab has developed expertise in a preclinical, surgical induction mouse model of TMJ OA that closely corresponds to the human condition and identified a three-step pathogenesis model linking mechanical damage to ECM changes and chondrocyte apoptosis that includes 1) the depletion of Collagen VI (Col VI) following surgically-induced TMJ OA 2) the proteolysis of a Col VI chondrocyte receptor, Neuron/Glial antigen 2 (NG2) and 3) the reduction of autophagy. The overall goal of our study is to test the hypothesis that injury-induced Col VI degeneration activates an NG2-dependent pathway that accelerates TMJ cartilage degeneration by suppressing autophagy. Based on the preliminary data included in this application, we have designed a research plan to mechanistically define how NG2 binding with Col VI is necessary for the maintenance of autophagy through activation of the mTORC1 pathway. The proposed work is innovative because it focuses on a novel molecular mechanism of chondrocyte function that contextually links matrix dysfunction with loss of a cytoprotective cellular mechanism implicated in the progression of TMJ OA. The significance of this research lies in the potential application to the clinical problems of TMJ OA and represents a leap forward in our knowledge of TMJ OA pathophysiology. We anticipate that the outcomes of our study will inform new therapeutic approaches with the potential to attenuate the progression of TMJ OA and restore TMJ health in patients that would otherwise require alloplastic total joint replacement.

摘要颞下颌关节骨性关节炎纤维软骨细胞的细胞-基质调节颞下颌关节（TMJ）疾病影响3-7%的人口和骨关节炎（OA）是与颞下颌关节功能障碍相关的最常见病理。颞下颌关节骨性关节炎是一种软骨疾病变性和软骨细胞凋亡。导致软骨细胞凋亡的关键因素之一是抑制自噬的细胞保护过程。自噬是最早的细胞反应之一 TMJ OA，并已被证明是一个可行的治疗目标，为减缓软骨的进展，退化知识上的一个主要空白是机械和炎症应激如何导致最终的抑制自噬、细胞凋亡和软骨退化。为了解决这一差距，我的实验室开发了临床前手术诱导TMJ OA小鼠模型的专业知识，该模型与人类非常相似并确定了一个三步发病机制模型，将机械损伤与ECM变化联系起来，软骨细胞凋亡，包括1）在关节炎诱导的TMJ后胶原VI（Col VI）的消耗 OA 2）Col VI软骨细胞受体神经元/神经胶质抗原2（NG 2）的蛋白水解，和3）神经元/神经胶质抗原2（NG 2）的减少。自噬我们研究的总体目标是检验损伤诱导的VI型胶原变性激活NG 2依赖性途径，通过抑制自噬加速TMJ软骨退化。根据本申请中包含的初步数据，我们设计了一个研究计划，机械地定义NG 2与Col VI的结合如何是维持自噬所必需的， mTORC 1通路的激活。这项工作是创新的，因为它集中在一个新的分子软骨细胞功能的机制，将基质功能障碍与细胞保护因子的丧失联系起来， TMJ OA进展中的细胞机制。本研究的意义在于潜在的应用，以临床问题的颞下颌关节骨性关节炎，并代表了一个飞跃，我们的知识颞下颌关节 OA病理生理学。我们预计，我们的研究结果将为新的治疗方法提供信息，减缓TMJ OA进展并恢复患者TMJ健康的潜力，需要异体全关节置换。