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

项目摘要 α 1-抗胰蛋白酶缺乏症（AATD）是肝脏疾病最常见的遗传原因， 儿童和最常见的肝衰竭和移植的遗传适应症， 儿科人群。然而，AATD相关肝病的临床过程是高度可变的。 大多数患有纯合子重度AATD（PiZZ）的婴儿在儿童早期临床恢复 通过未知的适应机制。流行病学研究表明， 外地的未决问题。它们是：（1）适应的机制是什么？ 错误折叠的AAT积聚在ER腔内？(2)适应机制是否仅仅 是针对错误折叠的AAT还是针对其他未折叠的蛋白质？（3）我们可以设计 直接使用这些适应机制的治疗策略？在这里，我们发现了一本小说 α 1-抗胰蛋白酶缺乏适应机制，ER蛋白毒性应激-m6 A通路或ERm 6A ：未折叠的α 1-抗胰蛋白酶蛋白积累诱导N6-腺苷甲基转移酶14 （胃L14）升高以增加C/EBP同源蛋白（CHOP）的m6 A mRNA甲基化， 其抑制CHOP翻译并减少其下游促凋亡蛋白的表达， 靶基因、细胞凋亡和肝损伤。我们认为ERm 6A调节ER蛋白毒性应激 在外延层面上，通过一种不同于以往任何其他机制的机制， 描述了ER蛋白毒性应激相关信号通路，包括众所周知的 典型的（转录和翻译水平）UPR途径。我们将检验中心假设 由未折叠蛋白质积累诱导的胃L14抑制细胞死亡和肝脏 通过调节CHOP 5′ UTR m6 A修饰（目的1.2）来降低肝毒性（目的1.1）。这项建议 解决了NICHD的使命，通过严格调查的分子机制， AATD诱导的肝损伤有可能改善大量儿童的健康状况。

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.