Defining Common Molecular Parameters For Onset and Progression of Osteoarthritis

定义骨关节炎发病和进展的常见分子参数

• 批准号: 8046767
• 负责人: MARY B GOLDRING
• 金额: $ 414.04万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046767
• 关键词: Achievement; Adult; Affect; Age-Months; Area; Bioinformatics; Cartilage; Cells; Chondrocytes; Chondrogenesis; Collagen; Collagen Type XI; Complex; Computer software; Coupled; DDR2 gene; Data; Data Set; Degenerative Disorder; Degenerative polyarthritis; Detection; Development; Differentiation and Growth; Disease; Disease model; Event; Gene Expression; Genetic; Genetic Models; Genome; Genomics; Human; Hypertrophy; Individual; Inflammation; Institution; Joints; Knee joint; Knowledge; Laboratories; Left; MAPK14 gene; MAPK8 gene; Maps; Medial meniscus structure; MicroRNAs; Modality; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Nature; Onset of illness; Operative Surgical Procedures; Pathway interactions; Pharmacologic Substance; Phase; Physiology; Proteins; Proteoglycan; Proteome; Proteomics; Publishing; RNA; Research Personnel; Role; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Site-Directed Mutagenesis; Staging; Stress; Surgical Models; Synovial Fluid; System; Technology; Therapeutic; Time; Tissues; articular cartilage; base; clinically relevant; collagenase; collagenase 3; design; effective therapy; extracellular; high throughput technology; innovation; joint injury; mouse model; new therapeutic target; novel; prevent; programs; public health relevance; response; transcription factor; transcription factor USF

DESCRIPTION (provided by applicant): This RC4 application in thematic area 1-- Applying Genomics and Other High Throughput Technologies-is an integrated, multi-disciplinary strategy to achieve a major "leap forward" in defining common biomolecular mechanisms underpinning osteoarthritis (OA). Rational therapeutic strategies against specific targets that determine the onset and severity of OA disease are severely lacking. Traditional prior efforts have primarily focused on single regulatory molecules, thereby hindering our ability to decipher the puzzle underlying the development of what is clearly a multifactorial disease or group of diseases. Prior achievements of our team of investigators have led to the development of novel murine models of OA disease and, of equal importance, also uncovered roles of specific transcription factors and upstream signaling molecules contributing to chondrocyte stress and differentiation. Among these are NF-B, Runx2, ESE-1/Elf3, GADD452, and DDR2, each of which impact on the expression of MMP-13, the major collagen-degrading enzyme in chondrocytes. Thus, our findings provide a conceptual framework that will be exploited to analyze unbiased genome-based and phospho-proteome screens across multiple mouse OA disease models. We hypothesize that stress- or inflammation-induced signals not only contribute to IRREVERSIBLE joint damage (progression) in OA, but importantly, also to the initiation/onset phase, wherein chondrocytes in articular cartilage leave their natural growth- and differentiation-arrested state. We will employ 3 carefully chosen murine OA models, each of which affect OA disease development by different inherent changes in chondrocyte function and physiology: (1) diminished expression of Runx2, a pivotal transcription factor that drives chondrocyte differentiation towards hypertrophy, and (2) loss of canonical NF-:B signaling, the major pathway orchestrating diverse responses to intracellular and extracellular stress, and (3) haploinsufficiency of type XI collagen in the cho/+ mutant mouse. Each of these 3 murine OA models will be subjected to the first integrated use of vanguard technologies of microRNA (miRNA) and gene expression arrays, phospho-protein proteomics (focusing initially on NF-:B, MAPK/ERK, p38, JNK, JAK/STAT, and Tak1/Smad cascades), and systems-level bioinformatics to define key networks and targets most commonly activated in genetic and post-traumatic murine OA. Importantly, the latter novel data will then be used to interrogate existing genome or proteome datasets from human OA cartilage, synovia and synovial fluids to uncover the conserved, clinically relevant targets in the context of the "whole joint" in OA disease development and progression. PUBLIC HEALTH RELEVANCE: This RC4 proposal (Thematic Area 1) involves a multi-disciplinary approach using powerful gene expression, miRNA, and single cell phospho-proteome screens that will give a comprehensive and integrated picture of the important regulatory networks in cartilage that impact on OA disease onset and progression. The innovative and coordinated efforts of multiple PIs at four different institutions will uncover novel 'common effectors' and critical networks across 3 murine models with post-traumatic or genetic OA. Moreover, interrogation against available human OA datasets will have clinically relevant impact in the context of the "whole joint" and uncover new therapeutic targets.

描述（由申请人提供）：主题领域1-应用基因组学和其他高通量技术-的RC 4应用程序是一个综合的多学科策略，以实现在定义骨关节炎（OA）基础上的常见生物分子机制方面的重大“飞跃”。目前严重缺乏针对特定靶点的合理治疗策略，这些靶点决定了OA疾病的发作和严重程度。传统的先前努力主要集中在单一的调节分子上，从而阻碍了我们破译明显是多因素疾病或疾病组的发展背后的谜题的能力。我们的研究团队先前的成就已经导致了OA疾病的新型小鼠模型的开发，并且同样重要的是，还发现了有助于软骨细胞应激和分化的特定转录因子和上游信号分子的作用。其中包括NF-B、Runx 2、ESE-1/Elf 3、GADD 452和DDR 2，它们中的每一个都影响软骨细胞中主要胶原降解酶MMP-13的表达。因此，我们的研究结果提供了一个概念框架，将被利用来分析无偏见的基因组为基础的和磷酸蛋白质组筛选在多个小鼠OA疾病模型。我们假设应力或炎症诱导的信号不仅导致OA中不可逆的关节损伤（进展），而且重要的是，还导致起始/发作阶段，其中关节软骨中的软骨细胞离开其自然生长和分化停滞状态。我们将采用3种精心选择的小鼠OA模型，每种模型通过软骨细胞功能和生理学的不同固有变化影响OA疾病的发展：（1）Runx 2（驱动软骨细胞向肥大分化的关键转录因子）的表达减少，和（2）经典NF-：B信号传导（协调对细胞内和细胞外应激的不同反应的主要途径）的丢失，和（3）cho/+突变小鼠中XI型胶原的单倍不足。这3种小鼠OA模型中的每一种都将首次综合使用microRNA（miRNA）和基因表达阵列、磷蛋白质组学（最初关注NF-：B、MAPK/ERK、p38、JNK、JAK/STAT和Tak 1/Smad级联）和系统水平生物信息学的先进技术，以确定遗传和创伤后小鼠OA中最常激活的关键网络和靶标。重要的是，后者的新数据将用于询问来自人OA软骨、滑膜和滑液的现有基因组或蛋白质组数据集，以揭示OA疾病发展和进展中“整个关节”背景下保守的临床相关靶标。 公共卫生关系：该RC 4提案（主题领域1）涉及使用强大的基因表达，miRNA和单细胞磷酸蛋白质组筛选的多学科方法，这些方法将全面综合地了解软骨中影响OA疾病发作和进展的重要调控网络。四个不同机构的多名PI的创新和协调努力将在3种创伤后或遗传性OA小鼠模型中发现新型“共同效应物”和关键网络。此外，针对可用的人类OA数据集的询问将在“整个关节”的背景下具有临床相关的影响，并发现新的治疗靶点。