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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：
10368995
负责人：
David Andrew Reed
金额：
$ 41.07万
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/10368995
关键词：
Address Affect Apoptosis Arthritis Attenuated Autophagocytosis Binding Biochemical Bioreactors CSPG4 gene 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 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 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