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）是老年人中最常见的退行性疾病，发病率迅速上升 50 岁以后，70 岁以后趋于平稳。OA 也是慢性疼痛的常见原因之一， 目前，对治疗策略的需求尚未得到满足。 为了改善 OA 患者的治疗效果，我们的最新工作确定了一系列人类 microRNA (miRNA)。 软骨并证明与强大的合成代谢作用有很强的相关性，这种作用是关节特异性的。 遵循远近轴梯度（踝关节高，髋关节低）。研究表明，关节的特性是： 这表明，不同关节中存在不同的 miRNA 谱。 我们在软骨中鉴定出的 miRNA 可能源自滑膜并参与维持关节 在目标 1 中，我将确定表达这些再生 miRNA 的滑膜细胞类型。 人类关节以及年龄对这些 miRNA 表达的影响 在目标 2 中，我将确定信号传导。 软骨中 miRNA 介导的合成代谢作用的负责途径以及年龄对这些作用的影响 我将进行基因集富集分析以确定 miRNA 介导的途径，然后使用 通过蛋白质组学来验证这些途径，我将确定 miRNA 介导的机制。 滑膜细胞通过其促进人类关节的内源性合成代谢作用，这是职业生涯增强的关键。 该奖项的主要内容将是计算生物信息学方面的培训，以分析由以下方法生成的复杂数据集： 该项目，以及衰老生物学方面的进一步培训，以了解衰老如何影响再生过程。 促进独立的进展，培训计划将包括以下课程/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 专业发展活动和指导在此详细说明。 该提案将由生物统计学教授李一菊博士团队进行。 生物信息学和统计学和生物信息学专家将作为主要导师，重点关注 Cathleen Colón 博士，弗吉尼亚州埃默里克，生物信息学、统计学和专业技能发展培训。 Kraus（杜克大学）和 Patrik Önnerfjord（瑞典隆德大学）将担任联合导师，他们将提供便利； 分别接受转化衰老研究、OA 研究和蛋白质组学方面的培训。 主要研究活动所在地杜克大学和杜克分子生理学研究所是 该奖项将使我能够阐明本提案中概述的研究和培训活动。 miRNA 对关节组织稳态的新贡献是这一研究领域的进展。 有望开发为旨在改善 OA 患者生活质量的新治疗策略。