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，由于人口老龄化，预计患病率将进一步增加。尽管已经确定了许多药物靶点，并且临床前研究已经显示出降低疾病严重程度的功效，但关于疾病修饰OA药物的临床试验已经失败。实验方法，如测试所选基因或蛋白质的表达模式中的疾病相关差异，并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：（i）它们仅提供了OA中发生的分子变化的选择性和有偏见的观点;（ii）在将这些发现整合到网络中并通过其作为OA过程驱动因素的相关性对目标进行优先排序方面没有成功的努力。该项目利用了（i）我们在整个成人年龄范围和OA发展的所有阶段的捐赠者中获得的人类膝关节组织和专业知识;（ii）人类膝关节组织库;（iii）转录组和表观遗传变化的大规模全基因组分析的技术进步，这提供了对软骨稳态的遗传景观产生公正和全面看法的机会，衰老和OA;（iv）我们用于多组学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）数据将产生新的签名，途径和软骨稳态，衰老和OA的关键调控因子。目标1.健康的软骨老化：识别软骨稳态和健康衰老的新型转录组学和表观基因组学（非编码RNA和DNA甲基化）标志物。目标二。OA相关变化：揭示OA中被破坏的通路和网络，并确定OA发病机制的主要调节因子。目标3.验证：确认基因和蛋白质表达的差异，分析OA发病机制主要驱动因素的调控和功能。影响力：据我们所知，这是第一个研究全基因组mRNA表达谱和全基因组表达调控因子（miR，其他非编码RNA，DNA甲基化）在横截面健康膝关节老化和OA中的项目。拟议的研究有可能导致发现（i）新的生物标志物;（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子集，从而产生个性化治疗方法。最终，这可能会导致干预措施，以减缓衰老，并确定治疗目标，以延迟或治疗OA。通过提供原始数据集，该项目还将为科学界提供资源。

 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.