The Role of MicroRNA in Osteoarthritis: Alzheimer's Administrative Supplement

项目摘要 阿尔茨海默病(AD)是最常见的与衰老相关的疾病之一，影响着550多万人 美国人65岁及以上，因此造成了巨大的社会经济负担。到目前为止，还没有治愈的方法 AD，由于我们对AD和衰老的生物学过程的了解有限。我们已经发现了两个 同源miRNAs，miR-204和miR-211，对于衰老的关节细胞维持健康的内稳态是必不可少的 以对抗骨关节炎(OA)的发病机制。有趣的是，具有双基因敲除(DKO)的小鼠模型 MIR-204和miR-211表现出多种病理改变，大多与年龄有关，如关节内的骨关节炎， 过熟性白内障伴破裂，葡萄膜黑变，视网膜发育不良，皮肤滤泡发育不良， 和心脏瓣膜心内膜病。特别是，dko的大脑似乎发生了加速衰老。 老鼠。因此，dKO小鼠可能代表了一种独特的、全面的衰老模型。深度测序 MiRNAs已经证明miR-204主要在大脑中表达，生物信息学分析显示 多个AD相关基因可能是miR-204/-211的靶点。考虑到多路老化 在dKO小鼠的表型中，我们假设miR-204和miR-211在脑中发挥重要作用 病理生理学和miR-204/-211功能丧失可能加重AD的发病。因此，我们 在本附录中提出两个具体目标，以扩大我们对miRNA在AD和AD这两种疾病的骨性关节炎中作用的研究 涉及衰老的生物过程的失调。在目标1中，我们将识别AD相关基因 以miR-204/-211为靶点，在目标2中，我们将确定miR-204/-211是否功能丧失 加重阿尔茨海默病小鼠模型的发病机制。从这项研究中发现的新见解将深化 我们对AD的理解和揭示了加速衰老是如何发生的，从而促进了 创新的治疗选择，以治疗包括AD和OA在内的许多与衰老相关的疾病。

Project Summary Alzheimer’s disease (AD) is one of the most common aging-related diseases, affecting more than 5.5 million Americans age 65 and older and thus creating enormous socioeconomic burden. To date there is no cure for AD, due to our limited understanding of AD and biological processes of aging. We have found that two homologous miRNAs, miR-204 and miR-211, are essential for aged joint cells to maintain healthy homeostasis to counteract osteoarthritis (OA) pathogenesis. Interestingly, the mouse model with double knockout (dKO) of miR-204 and miR-211 displayed multiple pathological changes, mostly aging-related, such as OA in joints, hypermature cataracts with rupture, uveal melanosis, and retinal dysplasia in eyes, follicular dysplasia in skins, and valvular endocardiosis in hearts. Particularly, accelerated aging appears to occur in the brain of the dKO mice. Thus, the dKO mice may represent a unique, comprehensive model of aging. Deep sequencing of miRNAs has demonstrated that miR-204 is dominantly expressed in brain, and bioinformatic analysis reveals that multiple AD-associated genes may be targeted by miR-204/-211. In consideration of multiplexed aging phenotypes in the dKO mice, we hypothesize that miR-204 and miR-211 play important roles in brain pathophysiology and miR-204/-211 loss-of-function may exacerbate the pathogenesis of AD. Thus, we propose two Specific Aims in this supplement to expand our study of miRNA role in OA on AD, both diseases involving dysregulation of biological processes of aging. In Aim 1, we will identify AD-associated genes targeted by miR-204/-211 in brain cells, and in Aim 2, we will determine if miR-204/-211 loss-of-function exacerbates AD pathogenesis in a mouse model of AD. New insights uncovered from this study will deepen our understanding of AD and shed light into how accelerated aging occurs, thus advancing the development of innovative therapeutic options to treat numerous aging-related disorders including AD and OA.