Integrative Omics analysis of human cartilage in aging and osteoarthritis

 描述(由申请人提供)：骨关节炎(OA)是最常见的肌肉骨骼疾病，预计由于人口老龄化，患病率将进一步上升。尽管已经确定了许多药物靶点，临床前研究也表明了在降低疾病严重性方面的有效性，但治疗骨性关节炎的药物的临床试验都以失败告终。实验方法，如检测选定基因或蛋白质与疾病相关的表达模式的差异，以及在临床前模型中分析这些分子的功能，已经产生了大量在OA中异常表达或激活的途径和分子。这些方法的局限性是：(1)它们仅对开放式获取过程中发生的分子变化提供选择性和有偏见的观点；(2)在将这些研究结果纳入网络并根据其作为开放式获取进程驱动力的相关性来确定目标的优先顺序方面，没有成功的努力。这个项目利用了(I)我们从整个成人年龄谱和OA发展的所有阶段的捐赠者那里获得人类膝关节组织的机会和专业知识；(Ii)人类膝关节组织库；(Iii)大规模、基因组范围的转录本和表观遗传学变化分析的技术进步，这为我们提供了对软骨内稳态、衰老和OA的遗传图景产生公正和全面的看法的机会；(Iv)我们用于多OMICS数据集的综合网络分析的新管道。我们的假设是，基因表达和表观遗传(miRNA、其他非编码RNA、DNA甲基化)数据将产生软骨内稳态、衰老和骨关节炎的新信号、新途径和关键调节因子。目的1.软骨健康老化：寻找软骨内稳态和健康衰老的新的转录和表观基因组(非编码RNA和DNA甲基化)标记物。目的2.骨关节炎相关改变：揭示骨关节炎中被破坏的通路和网络，确定骨关节炎发病的主要调控因素。目的3.验证：确认基因和蛋白表达的差异，分析OA发病的主要驱动因素的调节和功能。影响：据我们所知，这是第一个在横断面健康膝关节老化和骨关节炎中检查全基因组mRNA表达谱和全基因组表达调节因子(miRs，其他非编码RNA，DNA甲基化)的项目。这项拟议的研究有可能导致发现(I)新的生物标记物；(Ii)作为治疗靶点的新途径和主要分子开关；以及(Iii)具有独特表观遗传特征和基因表达模式的患者亚群，从而产生个性化治疗方法。最终，这可能导致对延缓衰老的干预，并确定延缓或治疗骨性关节炎的治疗靶点。通过公开原始数据集，该项目还将为科学界产生一个资源。

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common musculoskeletal disease with an expected further increase in prevalence due to population aging. Although many drug targets have been identified and preclinical studies have shown efficacy in reducing disease severity, clinical trials on disease modifying OA drugs have failed. Experimental approaches such as testing disease-related differences in expression patterns of selected genes or proteins and analyzing function of these molecules in preclinical models has yielded a large number of pathways and molecules that are abnormally expressed or activated in OA. The limitations of these approaches are (i) that they provide only a selective and biased view of molecular changes that occur in OA and (ii) there has been no successful effort in integrating these findings into networks and prioritizing targets by their relevance as drivers of the OA process. This project leverages (i) our access to and expertise in working with human knee tissues from donors across the entire adult age spectrum and at all stages of OA development; (ii) human knee tissue libraries; (iii) technical advances in large scale, genome wide analyses of transcriptomes and epigenetic changes, which provide the opportunity to generate an unbiased and comprehensive view of the genetic landscape of cartilage homeostasis, aging and OA; (iv) our novel pipeline for integrative network analysis of multi-Omics data sets. Our hypothesis is that the gene expression and epigenetic (miRNA, other non-coding RNA, DNA methylation) data will generate novel signatures, pathways and key regulators of cartilage homeostasis, aging and OA. Aim 1. Healthy cartilage aging: Identify novel transcriptomic and epigenomic (non-coding RNA and DNA methylation) markers of cartilage homeostasis and healthy aging. Aim 2. OA-related changes: Reveal pathways and networks that are disrupted in OA and identify principal regulators of OA pathogenesis. Aim 3. Validation: Confirm differences in gene and protein expression and analyze regulation and function of principal drivers of OA pathogenesis. Impact: To our knowledge, this is the first project to examine genome-wide mRNA expression profiles and genome-wide regulators of expression (miRs, other non-coding RNAs, DNA methylation) in cross-sectional healthy knee aging and OA. The proposed study has potential to lead to the discovery of (i) new biomarkers; (ii) novel pathways and principal molecular switches as therapeutic targets; and (iii) subsets of patients with unique epigenetic signatures and gene expression patterns, resulting in a personalized treatment approach. Ultimately this may lead to interventions to slow aging, and to the identification of therapeutic targets to delay or treat OA. By making the original data sets publicy available, the project will also generate a resource for the scientific community.