权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting GPR68 as a novel modulator of osteoarthritis

靶向 GPR68 作为骨关节炎的新型调节剂

基本信息

批准号：
10452259
负责人：
Mohd Nazir Khan
金额：
$ 12.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452259
关键词：
Acidity Acidosis Attenuated Biochemical Biological Assay Biomechanics Cartilage Cartilage Matrix Catabolism Chondrocytes Clinical Clinical Research Data Data Analyses Data Set Databases Degenerative polyarthritis Development Disease Disease Progression Environment Experimental Models Extravasation Family Foundations Future G-Protein-Coupled Receptors GPR4 gene GPR68 gene Gatekeeping Gene Expression Genes Genome Genotype Goals Histologic Human IL6 gene In Vitro Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Intervertebral disc structure Joints Lasers Lead Mechanical Stimulation Mechanical Stress Mechanics Medial meniscus structure Mediating Messenger RNA Modality Molecular Molecular Target Mus Musculoskeletal NOS2A gene Onset of illness Ontology Operative Surgical Procedures Orphan Osmolar Concentration PTGS2 gene Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Process Production Proteins Protons Public Domains Regulation Replacement Arthroplasty Resources Role Signal Transduction Stress Surface Synovial Fluid TNF gene Testing Tissues Ursidae Family Work arthropathies base bone cartilage degradation drug development druggable target experience experimental study extracellular genome sequencing in vivo interest knock-down lentiviral-mediated loss of function mechanical load mechanical signal mechanotransduction member novel novel therapeutic intervention prevent receptor receptor function small hairpin RNA small molecule therapeutic genome editing transcriptome sequencing

项目摘要

Clinical premise: Osteoarthritis (OA), the most common form of joint disorder, is a debilitating joint disease involving progressive cartilage degeneration, with no disease modifying therapy available. Thus, efforts to elucidate new molecular target and mechanism that can be utilized to prevent and/or treat the OA are of utmost importance. Recently, an orphan GPCR protein-the GPR68 has been identified and characterized in musculoskeletal tissues including bone and intervertebral disc, however its role in cartilage and OA is not known. Our preliminary analyses demonstrate that GPR68 was robustly expressed in cartilage derived from human OA patient and experimental model of OA in mice, indicating its role in OA pathogenesis. Using IDG/Pharos database, we identified `Inflammatory Process' a major GO term (Gene Ontology) associated with GPR68. In this project, we propose to establish the functional role of GPR68 in inflammatory signaling in osteoarthritic chondrocytes and ascertain its significance in OA pathogenesis. Scientific premise: We provide compelling preliminary evidence of the following: 1. GPR68 was robustly expressed in human and mice cartilage and its expression was significantly higher in OA cartilage compared to healthy cartilage; 2. GPR68 mRNA and protein levels was higher in high-grade OA cartilage as compared to low-grade OA cartilage; 3. Mechanical stimulation of primary human chondrocytes resulted in increased expression of GPR68; 4. Gpr68 expression was significantly higher in mice cartilage of surgically induced OA (DMM surgery) as compared to sham control; 5. IL1β stimulation of OA chondrocytes resulted in significantly increased expression of GPR68; 6. Knockdown of GPR68 in OA chondrocytes alleviated IL-1β induced expression of inflammatory genes. Hypothesis: GPR68 mediates inflammatory and catabolic effects leading to OA progression and thus suppression of GPR68 attenuates the inflammation and matrix degeneration in OA joints. Specific objectives: To verify this hypothesis, we will establish the functional role of GPR68 in inflammatory and catabolic pathways in human OA chondrocytes (Aim1). We will then define the role of Gpr68 in cartilage degradation in surgically induced osteoarthritis in vivo (Aim 2). Impact: Identifying the pathophysiological role of GPR68 in the regulation of chondrocyte inflammatory and catabolic activity will lead to the potential development of novel therapeutic strategies to treat OA, thus laying the foundation for future clinical study to establish a novel effective OA modifying drug.

临床前提：骨关节炎（OA）是最常见的关节疾病，是一种使人衰弱的关节疾病