Role of m6A modification in Alpha 1-antitrypsin deficiency induces liver disease

m6A 修饰在 Alpha 1-抗胰蛋白酶缺乏诱发肝病中的作用

• 批准号: 10188931
• 负责人: Juncheng Wei
• 金额: $ 22.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188931
• 关键词: 5' Untranslated Regions; ATF6 gene; Address; Adenosine; Apoptosis; Apoptotic; Attenuated; Biological; Cell Death; Child; Childhood; Chronic; Cirrhosis; Clinical; Development; Endoplasmic Reticulum; FDA approved; Fibrosis; Functional disorder; Genes; Genetic; Genetic Transcription; Genetic Translation; Health; Hepatic; Hepatotoxicity; Incidence; Infant; Inflammation; Inherited; Injury; Knock-out; Link; Liver; Liver Failure; Liver diseases; Measures; Mediating; Messenger RNA; Metabolic; Methylation; Methyltransferase; Mission; Mitochondria; Modification; Molecular; Mus; Mutation; National Institute of Child Health and Human Development; Nuclear Export; Obesity; Outcome; Pathway interactions; Pharmaceutical Preparations; Phenotype; Polymers; Population; Proteins; RNA Splicing; Regulation; Role; Signal Pathway; Site-Directed Mutagenesis; Stress; Testing; Therapeutic; Toxic effect; Translating; Translations; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; carcinogenesis; design; disorder prevention; early childhood; entacapone; epidemiology study; improved; liver injury; liver transplantation; misfolded protein; mouse model; mutant; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; protein degradation; protein expression; protein folding; proteotoxicity; response; trait; transcription factor; transcription factor CHOP

PROJECT SUMMARY Alpha1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and the most frequent inherited indication for liver failure and transplantation in the pediatric population. However, the clinical course of AATD-related liver disease is highly variable. The majority of infants with homozygous severe AATD (PiZZ) clinically recover in early childhood through the unknown adaptive mechanisms. Epidemiological studies give rise to three outstanding questions in the field. They are: (1) What are the mechanisms of adaptation to the misfolded AAT accumulation in the lumen of ER? (2) Do the mechanisms of adaptation only response to misfolded AAT or also target other unfolded proteins? and (3) Can we design therapeutic strategies to directly use these mechanisms of adaptation? Here, we identified a novel alpha1-antitrypsin deficiency adaptive mechanism, ER proteotoxic stress-m6A pathway or ERm6A : Unfolded Alpha1-antitrypsin protein accumulation induces N6-adenosine-methyltransferase 14 (METTL14) elevation to increase m6A mRNA methylation of C/EBP Homologous Protein (CHOP), which suppresses CHOP translation and reduces expression of its downstream pro-apoptotic target genes, apoptosis and liver injury. We propose that ERm6A regulates ER proteotoxic stress at the epitranscriptional level, through a mechanism that is distinct from any other previously described ER proteotoxic stress-associated signaling pathway, including the well-known canonical (transcriptional and translational level) UPR pathway. We will test the central hypothesis that METTL14, induced by unfolded protein accumulation, suppresses cell death and liver hepatotoxicity (Aim 1.1) by modulating CHOP 5′ UTR m6A modification (Aim 1.2). This proposal addresses the mission of the NICHD by rigorously investigating the molecular mechanisms of AATD-induced liver injury with the potential to improve health for large numbers of children.

项目摘要 alpha1-抗抗蛋白酶缺乏症（AATD）是肝病中最常见的遗传原因 儿童以及最常见的肝脏衰竭和移植指示 小儿种群。但是，与AATD相关的肝病的临床过程高度可变。 大多数纯合严重AATD（披萨）的婴儿在幼儿期临床康复 通过未知的自适应机制。流行病学研究引起了三个 该领域的杰出问题。它们是：（1）适应的机制是什么 错误折叠的AAT积累在ER的管腔中？ （2）仅执行适应机制 反应错误折叠的AAT或靶向其他展开的蛋白质？ （3）我们可以设计吗 直接使用这些适应机制的治疗策略？在这里，我们确定了一本小说 α1-抗抗蛋白酶缺乏自适应机制，ER蛋白毒性应激-M6A途径或ERM6A ：展开的α1-抗抗蛋白蛋白蛋白积累诱导N6-腺苷甲基转移酶14 （METTL14）升高以增加C/EBP同源蛋白（CHOP）的M6A mRNA甲基化， 抑制了CHOP翻译并降低其下游促凋亡的表达 靶基因，凋亡和肝损伤。我们建议ERM6A调节ER蛋白毒性应激 在上次卷曲级别，通过与以前任何其他任何其他机制不同 描述了ER蛋白毒性应激相关信号通路，包括众所周知的 规范（转录和翻译级别）UPR途径。我们将检验中心假设 由展开的蛋白质积累诱导的Mettl14抑制细胞死亡和肝脏 肝毒性（AIM 1.1）通过调节CHOP 5'UTR M6A修饰（AIM 1.2）。这个建议 通过严格研究的分子机制来解决NICHD的任务 AATD引起的肝损伤有可能改善大量儿童的健康。