Novel mechanisms of microRNA-mediated anabolic effects in age-related osteoarthritis

摘要 骨关节炎是老年人最常见的退行性疾病，发病率呈快速上升趋势。 50岁以后，70岁以后趋于平稳。骨性关节炎也是慢性疼痛的常见原因之一， 老年人身体残疾的主要原因。目前，对治疗策略的需求尚未得到满足。 以改善骨性关节炎患者的预后。我们的最新工作确定了人类体内的一系列microRNAs(MiRNAs) 并显示出与强大的合成新陈代谢作用密切相关。这种效果是特定于关节的，并且 遵循远端-近端轴的渐变(脚踝高，臀部低)。研究表明，关节的身份是 由滑膜细胞维持，在不同的关节中有不同的miRNA图谱。总而言之，这表明 我们在软骨中发现的miRNAs可能起源于滑膜，并参与维持关节 动态平衡。在目标1中，我将确定表达这些再生miRNAs的滑膜细胞类型 人类关节和年龄对这些miRNAs表达的影响。在目标2中，我将确定信令 软骨中miRNA介导的合成代谢效应的途径及年龄对其的影响 小路。我将进行基因集浓缩分析，以确定miRNA介导的途径，然后使用 蛋白质组学来验证这些途径。通过这个项目，我将确定miRNA介导的机制 滑膜细胞通过它促进人体关节的内源性合成代谢作用。关键的职业提升 该奖项将包括计算生物信息学方面的培训，以分析由 该项目，以及进一步的衰老生物学培训，以了解衰老如何影响再生过程。至 促进独立的进展，培训计划将包括课程作业/讲习班 计算生物信息学和衰老生物学，广泛的内部和外部科学会议，以及职业生涯 职业发展活动和辅导。本文件中详述的研究和职业发展计划 提案将与一支优秀的导师团队一起进行。生物统计学与生物统计学教授李毅菊博士 生物信息学和统计学和生物信息学专家，将担任主要导师，并专注于 生物信息学、统计学和专业技能发展方面的培训。凯瑟琳·科隆-埃默里奇博士，弗吉尼亚州 Kraus(Duke)和PatrikÖnnerfjord(瑞典隆德大学)将担任共同导师；他们将促进 分别接受翻译衰老研究、骨关节炎研究和蛋白质组学方面的培训。中国的环境 主要研究活动所在的杜克大学和杜克分子生理学研究所 非常适合于本提案中概述的研究和培训活动。这项裁决将使我能够澄清 MiRNAs对关节组织动态平衡的新贡献。这一研究领域的进步具有 有潜力发展为旨在改善骨性关节炎患者生活质量的新治疗策略。

Abstract Osteoarthritis (OA) is the most prevalent degenerative disease in older adults with the incidence rising rapidly after age 50 and leveling off after age 70. OA is also one of the common causes of chronic pain and the leading cause of physical disability in older adults. Currently, there is an unmet need for therapeutic strategies to improve the outcome for patients with OA. Our latest work identifies a list of microRNAs (miRNAs) in human cartilage and demonstrates a strong association with a robust anabolic effect. This effect is joint-specific and follows a distal-proximal axis gradient (high in ankle and low in hip). Studies show that a joint's identity is maintained by synovial cells and that there is a distinct miRNA profile in different joints. Together, this suggests that the miRNAs we identified in cartilage may originate from synovium and be involved in maintaining joint homeostasis. In Aim 1, I will determine the synovial cell types that express these regenerative miRNAs within human joints and the effects of age on the expression of these miRNAs. In Aim 2, I will determine the signaling pathways responsible for the miRNA-mediated anabolic effects in cartilage and the effects of age on these pathways. I will conduct gene set enrichment analysis to determine miRNA-mediated pathways and then use proteomics to validate these pathways. Through this project, I will determine the miRNA-mediated mechanisms by which synovial cells promote endogenous anabolic effects in the human joint. The key career enhancement of this award will be the training in computational bioinformatics to analyze the complex datasets generated by the project, and further training in aging biology to understand how aging impacts the regeneration process. To facilitate progress toward independence, the training plan will include the coursework/workshops in computational bioinformatics and aging biology, extensive internal and external scientific meetings, and career professional development activities and mentorship. The research and career development plan detailed in this proposal will be conducted with a team of outstanding mentors. Dr. Yi-Ju Li, a professor of Biostatistics & Bioinformatics and an expert in statistics and bioinformatics, will serve as the primary mentor and focus on the training in bioinformatics, statistics, and professional skill development. Drs. Cathleen Colón -Emeric, Virginia Kraus (Duke), and Patrik Önnerfjord (Lund University, Sweden) will serve as co-mentors; they will facilitate training in translational aging research, OA research, and proteomics, respectively. The environment at the Duke University and Duke Molecular Physiology Institute, where the main research activities are located, are ideal for the research and training activities outlined in this proposal. This award will enable me to elucidate the novel contributions of miRNAs to joint tissue homeostasis. Advancements in this area of research have the potential to develop as new therapeutic strategies aimed at improving the quality of life for patients with OA.