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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要骨关节炎 (OA) 是最常见的退行性关节疾病，影响数百万人并导致巨大的经济负担。目前尚无疾病修饰疗法由于对 OA 进展的遗传因素和途径的了解有限，因此可用于 OA。因此，全面了解驱动 OA 发病机制的信号通路将促进早期诊断和疾病修饰疗法的创新。该提案将进一步推动分子粘附 G 蛋白偶联受体 G6 (Adgrg6) 基因的基因突变小鼠的表征。 ADGRG6 在人类和小鼠的关节软骨中富集，我们已经证明它参与人类骨关节炎。小鼠关节软骨中 Adgrg6 的缺失会导致类似 OA 的关节病理学，并且 cAMP 和 STAT3 信号通路失调。有趣的是，cAMP 信号传导以前是表明可驱动软骨保护机制，并且 STAT3 激活与 OA 的发展相关人类。基于这些新发现，我们假设关节软骨的稳态需要精确的 cAMP 和 STAT3 信号传导的调节。该假设将在三个具体目标下进行检验： 1. 我们将使用新型 Gs 耦合 DREADD 特异性激活关节软骨中的 cAMP 信号传导小鼠，并确定 cAMP 信号传导调节的转录网络。我们将确定 Adgrg6 突变小鼠和创伤后 OA 发育过程中 cAMP 信号传导的细胞效应器 OA小鼠模型。 2. 我们将使用以下方法确定 OA 进展过程中 STAT3 介导的信号传导的下游效应器通过分析 STAT3 依赖性基因调控建立创伤后 OA 小鼠模型。 3. 我们将确定靶向STAT3和cAMP信号通路治疗OA样疾病的疗效使用 OA 创伤后小鼠模型进行关节病理学研究。我们将利用创新药物针对这些途径的局部、缓慢释放的疾病修饰疗法的方法。总而言之，这项拟议的研究将利用小鼠遗传学，结合现代基因组学和定义 cAMP 和 STAT3 信号在关节软骨稳态中作用的药物方法和 OA 发病机制，这可能会加速我们对人类 OA 的诊断和治疗。