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

项目摘要 阿尔茨海默病（AD）是最常见的与衰老有关的疾病之一，影响超过550万人 65岁及以上的美国人，从而造成巨大的社会经济负担。迄今为止， AD，由于我们对AD和衰老的生物学过程的了解有限。我们发现， 同源miRNAs，miR-204和miR-211，对于老年关节细胞维持健康的稳态是必需的 以对抗骨关节炎（OA）发病机制。有趣的是，具有双敲除（dKO）的小鼠模型， miR-204和miR-211显示多种病理变化，大多数与衰老相关，如关节OA， 过熟白内障破裂、葡萄膜黑变病和眼睛中的视网膜发育不良、皮肤中的滤泡发育不良， 和心脏瓣膜性心内膜炎。特别是，加速老化似乎发生在dKO的大脑中， 小鼠因此，dKO小鼠可能代表了一种独特的、全面的衰老模型。的深度测序 miRNAs已经证明miR-204主要在脑中表达，生物信息学分析显示， miR-204/-211可能靶向多种AD相关基因。考虑到多重老化 在dKO小鼠中，我们假设miR-204和miR-211在脑组织中起重要作用， 病理生理学和miR-204/-211功能丧失可能加剧AD的发病机制。因此我们 在本补充中提出了两个具体目标，以扩大我们在OA和AD中miRNA作用的研究，这两种疾病 涉及衰老的生物过程失调。在目标1中，我们将识别AD相关基因 在目标2中，我们将确定miR-204/-211功能丧失是否与脑细胞中的miR-204/-211靶向相关。 加重AD小鼠模型中的AD发病机制。从这项研究中发现的新见解将加深 我们对AD的理解，揭示了加速衰老是如何发生的，从而推动了 创新的治疗选择，以治疗许多与衰老有关的疾病，包括AD和OA。

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.