Analyzing the role of cAMP and STAT3 signaling in cartilage homeostasis and osteoarthritis development

分析 cAMP 和 STAT3 信号在软骨稳态和骨关节炎发展中的作用

• 批准号: 10822167
• 负责人: Zhaoyang Liu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-14 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10822167
• 关键词: Ablation; Acceleration; Adhesions; Affect; Atlases; Automobile Driving; Bioinformatics; Cartilage; Catabolic Process; Catalogs; Cells; ChIP-seq; Clozapine; Coupled; Cyclic AMP; Degenerative polyarthritis; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Formulations; Early Diagnosis; Engineering; Financial Hardship; Forskolin; Functional disorder; G-Protein-Coupled Receptors; Gene Expression Regulation; Genes; Genetic; Genetic Engineering; Genetic Recombination; Genetic Transcription; Genomics; Heterogeneity; Homeostasis; Human; Joints; Medial meniscus structure; Mediating; Mentors; Modernization; Molecular; Mus; Mutant Strains Mice; Natural History; Oxides; Pain management; Pathogenesis; Pathology; Pathway interactions; Persons; Pharmacologic Substance; Pharmacy (field); Regulation; Replacement Arthroplasty; Reporting; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid; Stat3 Signaling Pathway; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transcriptional Regulation; Transgenic Mice; Traumatic Arthropathy; Work; articular cartilage; career; chondroprotection; designer receptors exclusively activated by designer drugs; disability; efficacy evaluation; efficacy testing; experimental study; functional genomics; genetic approach; human model; innovation; interest; lipid nanoparticle; loss of function; mouse genetics; mouse model; mutant mouse model; nanoparticle drug; novel; postnatal; single-cell RNA sequencing; small molecule; targeted delivery; targeted treatment; training opportunity

Project Summary Osteoarthritis (OA) is the most common form of degenerative joint disease affecting millions of people worldwide and lead to a tremendous financial burden. Currently there are no disease modifying therapies available for OA, due to limited understanding of the genetic factors and pathways underling OA progression. Therefore, a comprehensive understanding of signaling pathways driving the pathogenesis of OA will motivate innovation for early diagnosis and disease modifying therapeutics. This proposal will further the molecular characterization of a genetic mutant mouse of the Adhesion G protein-coupled receptor G6 (Adgrg6) gene. ADGRG6 is enriched in articular cartilage in human and mouse, and we have demonstrated its involvement in human OA. Loss of Adgrg6 in the articular cartilage in mouse leads to OA-like joint pathology, and dysregulation of both cAMP and STAT3 signaling pathway. Interestingly, cAMP signaling is previously indicated to drive chondroprotective mechanisms, and STAT3 activation is associated with OA development in human. Based on these novel findings, we hypothesize that homeostasis of articular cartilage requires precise regulation of both cAMP and STAT3 signaling. This hypothesis will be tested under three specific aims: 1. We will specifically activate cAMP signaling in articular cartilage using a novel Gs-coupled DREADD mouse, and determine the transcriptional network regulated by cAMP signaling. We will determine the cellular effectors of cAMP signaling during OA development in Adgrg6 mutant mice and in post-traumatic mouse model of OA. 2. We will determine the downstream effectors of STAT3-mediated signaling during OA progression using the post-traumatic mouse model of OA by analysis of STAT3 dependent gene regulation. 3. We will determine the efficacy of targeting STAT3 and cAMP signaling pathways for treatment of OA-like joint pathology using the post-traumatic mouse model of OA. We will utilize innovative pharmaceutical approaches for localized, slow-release delivery of disease modifying therapies targeting these pathways. Taken together, this proposed study will utilize mouse genetics, combined with modern genomics and pharmaceutic approaches to define the role of cAMP and STAT3 signaling in articular cartilage homeostasis and OA pathogenesis, which may accelerate our diagnosis and treatment of human OA.

项目摘要 骨关节炎（OA）是影响数百万人的退化性关节疾病的最常见形式 全球，导致巨大的财务负担。目前没有修改疗法的疾病 由于对OA进展的遗传因素和途径的了解有限，可用于OA。 因此，对驱动OA发病机理的信号通路的全面理解将激励 早期诊断和疾病修饰治疗剂的创新。该建议将进一步分子 粘附G蛋白偶联受体G6（ADGRG6）基因的遗传突变小鼠的表征。 ADGRG6富含人和小鼠的关节软骨，我们已经证明了它参与 人OA。小鼠关节软骨中ADGRG6的丧失导致OA样关节病理学，并且 CAMP和STAT3信号通路的失调。有趣的是，训练营的信号以前是 指示可以驱动软骨保护机制，而STAT3激活与OA的发展有关 人类。基于这些新颖的发现，我们假设关节软骨的稳态需要精确 CAMP和STAT3信号的调节。该假设将根据三个具体目的进行检验： 1。我们将使用新型的GS耦合Dreadd专门激活关节软骨中的CAMP信号传导 鼠标，并确定由CAMP信号调节的转录网络。我们将确定 ADGRG6突变小鼠OA发育过程中营地信号传导的细胞效应子和创伤后 OA的鼠标模型。 2。我们将使用使用该OA进展过程中STAT3介导的信号传导的下游效应子 通过分析STAT3依赖基因调控，创伤后小鼠模型。 3。我们将确定靶向STAT3和CAMP信号通路的疗效 使用OA的创伤后小鼠模型的关节病理。我们将利用创新的药品 针对这些途径的局部，缓释疾病的局部缓释疗法的方法。 综上所述，这项拟议的研究将利用小鼠遗传学，并结合现代基因组学和 定义CAMP和STAT3信号在关节软骨稳态中的作用的药物方法 OA发病机理，这可能会加速我们对人OA的诊断和治疗。