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CCR7 and its ligands in Osteoarthritis

CCR7 及其配体在骨关节炎中的作用

基本信息

批准号：
8870910
负责人：
Carla Rose Scanzello
金额：
$ 21.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8870910
关键词：
Address Adult Animal Model Anti-Inflammatory Agents Arthralgia Arthritis Automobile Driving Bone remodeling CCL19 gene CCL21 gene Cartilage Chimeric Proteins Chronic Clinical Confocal Microscopy Data Degenerative polyarthritis Dendritic Cells Development Disease Flow Cytometry Functional disorder Gene Expression Generations Histopathology Human Immunoglobulin G Incidence Inflammation Inflammatory Joints Knee Knee Injuries Knee Osteoarthritis Knee joint Knock-out Lead Leukocytes Ligands Locomotion Lymphocyte Measures Medial meniscus structure Medical Meniscus structure of joint Messenger RNA Methods Modeling Monitor Mus Operative Surgical Procedures Outcome Pain Pathway interactions Patients Pattern Population Proteins Rehabilitation therapy Replacement Arthroplasty Research Risk Role Severities Speed Staging Symptoms Synovial Cell Synovial Membrane Synovitis Testing Time Tissues Transcript Travel Wild Type Mouse advanced disease bone cartilage degradation chemokine chemokine receptor disability effective therapy experience improved joint destruction joint injury light microscopy microCT monocyte new therapeutic target novel prevent public health relevance receptor sham surgery therapeutic target treatment strategy vibration

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a leading cause of disability in adults, and is characterized by chronic progressive cartilage damage and bony remodeling. Current treatment options are limited, do not prevent progressive joint damage, and factors related to joint dysfunction are poorly understood. Low-grade inflammation of the joint lining tissue (synovial membrane) is common in OA, and has been associated with severity of knee joint dysfunction, pain, and progression of cartilage loss. This suggests that synovial inflammation could be targeted to reduce both symptoms and progression of OA. We have recently identified expression of the chemokine receptor CCR7 and its two ligands (CCL19 and CCL21) in the synovial membrane of knee OA patients, including patients with early-stage OA knee OA. CCR7 is involved in the recruitment of multiple leukocyte populations suggesting it may promote development and perpetuation of synovial inflammation. In this proposal, we will test the hypothesis that CCR7 promotes synovial inflammation, cartilage damage and bone remodeling in OA, and impacts development of OA related disability, using the well-established murine destabilization of the medial meniscus (DMM) model. In the first aim, OA development will be monitored in mice deficient in CCR7 expression (CCR7 -/-) compared to C57BL/6 wild-type controls. Wild-type mice will also be treated with a fusion protein which counteracts the activity of CCL19. Cartilage and bone changes will be measured by histopathology and micro-CT, while synovial inflammation will be measured by gene expression and flow cytometry. These outcomes will be measured at 2, 4, 8, and 16 weeks post-DMM surgery, and compared to sham-operated and unoperated controls. Locomotion and normal activity (climbing, distance traveled, speed of locomotion) will be measured longitudinally every 4 weeks up to 16 weeks post- DMM and sham surgery, as a reflection of OA-related disability. In the second aim, expression levels and cellular distribution of CCR7 and its ligands will be evaluated in joint tissues from mice subjected to DMM or sham surgery, and in humans with and without OA. Results of this study will support subsequent proposals to understand specific mechanisms by which CCR7 impacts OA, and test pharmacologic CCR7 blockade intra-articularly.