The impact of RNA chemical modifications on polycystic kidney disease progression

摘要 常染色体显性遗传性多囊肾病(ADPKD)是最常见的单基因遗传病之一 人类疾病。近60万美国人受到这种毁灭性疾病的影响。 不幸的是，治疗选择有限。为了解决这一巨大的未得到满足的需求，我们将探索一种 新的治疗机会，包括靶向RNA化学修饰途径。现在已经有了 很明显，像DNA一样，RNA也经历了动态的化学变化，影响了它的 加工和功能。在初步分析中，我们发现来自囊性肾脏的mrna表现出 更高水平的称为m6A的特定RNA修饰，它指的是第6位的甲基化 腺苷中的氮。此外，我们注意到，通过删除关键的METTL3来降低m6A水平 介导这种修饰的酶可以改善临床前的PKD。进一步的机理研究 提出了一种新的假说，即降低m6A水平可以通过减少M6A的翻译来缓解PKD 致病基因。基于这些有希望的观察，我们建议：(A)使用补充性 最终确认METTL3/m6A通路为新通路的遗传学和药学方法 ADPKD的药物靶点。(B)鉴定ADPKD中受m6A调控的致病蛋白质组。总而言之， RNA修饰是一个在生理学和疾病中具有广泛意义的新兴领域，但其 对肾脏的影响尚不清楚。我们是第一个解决这些基本知识差距的人。 基于我们在RNA和ASO生物学方面的优势，我们还将发现一种新的药物靶点 ADPKD.

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is amongst the most common monogenetic human disorders. Nearly 600,000 Americans are affected by this devastating condition. Unfortunately, treatment options are limited. To address this large unmet need, we will explore a novel therapeutic opportunity involving targeting the RNA chemical modification pathway. It has now become clear that, like DNA, RNA also undergoes dynamic chemical changes that impacts its processing and function. In preliminary analysis we found that mRNAs from cystic kidneys exhibit higher levels of a specific RNA modification called m6A, which refers to methylation of the 6th nitrogen in adenosine. Moreover, we noted that reducing m6A levels by deleting Mettl3, a key enzyme that mediates this modification, ameliorates preclinical PKD. Further mechanistic studies suggested a novel hypothesis that lowering m6A levels alleviates PKD by reducing translation of pathogenic mRNAs. Based on these promising observations, we propose to: (a) use complementary genetic and pharmaceutical approaches to conclusively validate the Mettl3/m6A pathway as new drug target in ADPKD. (b) Identify the m6A-regulated pathogenic proteome in ADPKD. In summary, RNA modification is an emerging field with broad implications in physiology and disease, yet its impact on kidneys is unknown. We are the first to address these fundamental knowledge gaps. Building on our strengths in RNA and ASO biology, we will also uncover a novel drug target for ADPKD.