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

microRNA介导的年龄相关骨关节炎合成代谢作用的新机制

• 批准号: 10663670
• 负责人: Ming-Feng Hsueh
• 金额: $ 12.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663670
• 关键词: Age; Aging; Animal Model; Animals; Ankle; Area; Arthritis; Award; Bioinformatics; Biology of Aging; Biometry; Cartilage; Cell Separation; Cells; Clinical Trials; Colon; Data; Data Analyses; Data Set; Degenerative Disorder; Degenerative polyarthritis; Development; Development Plans; Distal; Educational Status; Educational workshop; Elderly; Environment; Fibroblasts; Future; Gene set enrichment analysis; Goals; Health; Hip Joint; Hip region structure; Homeostasis; Human; Incidence; Injury; Joints; Knowledge; Macrophage; Mediating; Mentored Research Scientist Development Award; Mentors; Mentorship; MicroRNAs; Molecular; Morbidity - disease rate; Musculoskeletal; Natural regeneration; Older Population; Pathway Analysis; Pathway interactions; Patient-Focused Outcomes; Patients; Physiology; Population; Process; Proteins; Proteomics; Quality of life; Research; Research Activity; Research Personnel; Science; Signal Pathway; Source; Stress; Sweden; Synovial Cell; Synovial Membrane; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Training; Training Activity; Translational Research; Universities; Virginia; Work; age effect; age related; aging population; ankle joint; appendage; career; career development; cell type; chronic pain; complex data; fighting; improved; improved outcome; injury and repair; joint destruction; joint inflammation; joint injury; limb regeneration; meetings; neutrophil; novel; novel therapeutic intervention; physically handicapped; prevent; professor; recruit; regenerative; regenerative therapy; research and development; resilience; response; skill acquisition; skills; statistics; therapeutic miRNA; therapy development

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.

抽象的 骨关节炎（OA）是老年人中最普遍的退行性疾病，事件迅速增加 50岁以后并在70岁以后升级。OA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，对治疗策略的需求未满足 改善OA患者的结果。我们的最新作品确定了人类中的microRNA（miRNA）清单 软骨并表现出与强大的合成代谢作用的密切关联。这种效果是特定于联合的， 遵循远端轴轴梯度（脚踝高，臀部低）。研究表明，联合的身份是 由滑膜细胞维持，并且在不同的接头中存在明显的miRNA谱。在一起，这表明 我们在软骨中鉴定的miRNA可能起源于滑膜，并参与保持关节 稳态。在AIM 1中，我将确定表达这些再生miRNA的滑细胞类型 人类关节和年龄对这些miRNA表达的影响。在AIM 2中，我将确定信号传导 负责miRNA介导的软骨中的合成代谢作用以及年龄对这些的影响的途径 途径。我将进行基因集富集分析以确定miRNA介导的途径，然后使用 蛋白质组学验证这些途径。通过这个项目，我将确定miRNA介导的机制 滑膜细胞在人关节中促进内源性合成代谢作用。关键职业增强 该奖项将是计算生物信息学的培训，以分析由 该项目，以及对衰老生物学的进一步培训，以了解衰老如何影响再生过程。到 促进独立进步，培训计划将包括课程/讲习班 计算生物信息学和老化生物学，广泛的内部和外部科学会议以及职业 专业发展活动和心态。其中详细介绍了研究和职业发展计划 提案将与杰出导师团队一起进行。 Yi-Ju Li博士，生物统计学教授＆ 生物信息学和统计和生物信息学专家将成为主要的心理，并专注于 在生物信息学，统计和专业技能开发方面的培训。博士。凯瑟·科隆（CathleenColón） - 弗吉尼亚州 克劳斯（杜克大学）和帕特里克·Önnerfjord（瑞典隆德大学）将担任联合会。他们将有便利 分别对翻译衰老研究，OA研究和蛋白质组学的培训。环境 主要研究活动所在的杜克大学和杜克分子生理研究所是 该提案中概述的研究和培训活动的理想选择。这个奖项将使我能够阐明 miRNA对关节组织稳态的新贡献。研究领域的进步具有 发展为新的治疗策略的潜力，旨在改善OA患者的生活质量。