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）是关节疾病的最常见形式，是一种虚弱的关节疾病涉及进行性软骨变性，没有可用的疾病阐明可用于预防和/或治疗OARE的新分子靶和机制很重要。肌肉骨骼组织在内，包括骨骼和椎间盘，是软骨中的作用，而OA尚不清楚。我们的初步分析表明，GPR68在源自人OA的软骨中强烈表达 OA的患者和实验模型，表明其在宣誓中的作用数据库，我们确定了与GPR68相关的主要GO术语（基因本体）这个项目，我们建议确定GPR68在炎症性信号中的功能作用软骨细胞并确定其在OA发病机理中的重要性。科学前提：我们提供以下令人信服的预启示证据：1。GPR68坚固与人类和小鼠软骨表达，与表达相比，软骨的表达显着很高健康的软骨；2。GPR68mRNA和蛋白质水平是高级OA软骨低度OA软骨； 3。 GPR68的表达; （DMM手术）与假对照相比。 GPR68的表达增加； 68 炎症基因的表达。假设：GPR68介导炎症和分解代谢作用，从而导致OA进展，从而 GPR68的含量减弱了OA关节中的炎症和基质变性。特定目标：为了验证这一假设，我们将确定GPR68在炎症中的功能作用和人OA软骨细胞中的分解代谢途径（AIM1）。体内手术性肠道关节炎的降解（AIM 2）。影响：确定GPR68在软骨细胞炎症调节中的病理生理作用和分解代谢活性将导致新型治疗策略的潜在发展处理OA，从而铺设未来临床研究的基础，建立了一种新型有效的OA修饰药物。