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The impact of RNA chemical modifications on polycystic kidney disease progression

RNA化学修饰对多囊肾病进展的影响

基本信息

批准号：
10532802
负责人：
Vishal Patel
金额：
$ 42.42万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-11 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532802
关键词：
Ablation Address Adenosine Adult Affect Alleles American Antisense Oligonucleotides Attenuated Autosomal Dominant Polycystic Kidney Biology Cells Chemical Dynamics Chemicals Chronic Cyclic AMP Cyst Cystic kidney DNA Disease Disease Progression Disease model Enzymes Epigenetic Process Epithelial cyst Event Exhibits Gene Expression Genetic Genetic Code Genetic Diseases Goals Growth Half-Life Human Immunoprecipitation Kidney Knockout Mice Knowledge Mediating Messenger RNA Metabolic Methionine Methylation Methyltransferase MicroRNAs Modeling Modification Mus Nitrogen Nucleotides Oncogenes Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiology Polycystic Kidney Diseases Property Proteins Proteome Proteomics Proxy RNA RNA immunoprecipitation sequencing Reaction Renal tubule structure S-Adenosylhomocysteine S-Adenosylmethionine Safety Signal Transduction Testing Tissues Transcript Translational Repression Translations Treatment Efficacy Tubular formation Up-Regulation Vasopressin Receptor Wild Type Mouse c-myc Genes clinically relevant comparative design epitranscriptomics fascinate inhibitor innovation insight loss of function mRNA Translation mouse model new therapeutic target novel novel drug class novel therapeutics overexpression pre-clinical ribosome profiling therapeutic evaluation tolvaptan

项目摘要

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.

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满足的需求，我们将探索涉及靶向RNA化学修饰途径的新的治疗机会。现已很明显，像DNA一样，RNA也会经历动态的化学变化，影响其加工和功能。在初步分析中，我们发现来自囊性肾的mRNA表现出更高水平的特定RNA修饰称为m6 A，这是指甲基化的第6位，腺苷中的氮。此外，我们注意到，通过删除Mettl 3来降低m6 A水平，介导这种修饰的酶，改善临床前PKD。进一步的机制研究提出了一种新的假设，即降低m6 A水平通过减少蛋白质的翻译来减轻PKD。致病基因基于这些有希望的观察结果，我们建议：（a）使用互补的基因和药物的方法来最终验证Mettl 3/m6 A途径作为新的 ADPKD的药物靶点。(b)鉴定ADPKD中m6 A调节的致病蛋白质组总的来说， RNA修饰是一个新兴的领域，在生理学和疾病中具有广泛的意义，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和阿索生物学方面的优势，我们还将发现一种新的药物靶点， ADPKD。