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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涉及进行性软骨退变，没有疾病修正疗法可用。因此，努力实现以下目标阐明可用于预防和/或治疗骨性关节炎的新的分子靶点和机制是非常重要的重要性。最近，一种孤儿蛋白GPR68被发现并鉴定了其特性。肌肉骨骼组织包括骨和椎间盘，但其在软骨和骨性关节炎中的作用尚不清楚。我们的初步分析表明，GPR68在人骨性关节炎的软骨中有很强的表达小鼠骨性关节炎的患者和实验模型，提示其在骨性关节炎发病机制中的作用。使用IDG/航标灯在数据库中，我们确定了与GPR68相关的一个主要的GO术语(基因本体论)：“炎症过程”。在……里面在这个项目中，我们建议建立GPR68在骨关节炎炎症信号转导中的功能作用。并探讨其在骨性关节炎发病机制中的意义。科学前提：我们提供了令人信服的以下初步证据：1.GPR68表现强劲在人和小鼠软骨中表达，在骨性关节炎软骨中的表达显著高于 2.高级别骨关节炎软骨中GPR68mRNA和蛋白的表达水平均高于正常对照组 3.机械刺激原代人软骨细胞导致软骨细胞数量增加 GPR68在手术诱导的骨性关节炎小鼠软骨中的表达显著升高 (5)IL-1β刺激骨性关节炎软骨细胞 GPR68基因在骨性关节炎软骨细胞中的表达增强抑制IL-1β诱导的骨关节炎软骨细胞炎症基因的表达。假设：GPR68介导炎性和分解代谢效应导致骨性关节炎进展，从而抑制GPR68可减轻骨关节炎关节的炎症和基质变性。具体目的：为了验证这一假说，我们将确定GPR68在炎症中的功能作用和人骨关节炎软骨细胞的分解代谢途径(Aim1)。然后我们将确定GPR68在软骨中的作用手术诱发的骨性关节炎在体内的降解(目标2)。影响：确定GPR68在调节软骨细胞炎症和炎症中的病理生理作用分解代谢活性将导致治疗骨性关节炎的新治疗策略的潜在发展，从而奠定为今后临床研究建立一种新型有效的骨性关节炎修饰药物奠定了基础。