RNA editing in islet function and inflammation

RNA编辑是一个基本的细胞过程，涉及一些腺苷的脱氨基， 腺苷脱氨酶Adar 1（阿达尔）和Adar 2（ADARB 1）将RNA转化为肌苷。 最近的研究表明，RNA编辑的关键作用是破坏双链RNA， 由插入基因组中的反转录元件产生的双链RNA（dsRNA）结构， 在表达的基因中定位。由这样的序列构型形成的dsRNA是一种双链RNA。 一种古老的抗病毒干扰素反应的强大而危险的激活剂，这可能导致 致病性炎症虽然RNA编辑已经在一些器官中进行了研究， 在癌症中，关于阿达尔酶在胰岛细胞功能中的作用知之甚少， 健康我们的目标是阐明RNA编辑在胰岛中的作用，特别是在α和β细胞中， β细胞引人注目的是，1型糖尿病（T1D）的GWAS研究揭示了保护性变异 IFIH1/MDA5是一种胞质受体，可识别来自 病毒或内源性来源，并激发炎症反应。因此，缺陷RNA编辑 原则上可有助于自身免疫之前的胰岛抗病毒应答。我们 假设β细胞中受损RNA编辑和内源性dsRNA的积累 触发IFIH 1依赖性干扰素反应，导致胰岛炎症，从而导致β 细胞功能障碍和潜在的自身免疫。在我们的初步调查中，我们发现， 体内成年小鼠β细胞或人类胰岛中A-to-IRNA编辑的破坏引发了一种新的免疫抑制剂， 干扰素应答在Adar 1缺陷β细胞的小鼠中，这会导致大规模免疫 免疫应答定位于胰岛，包括先天免疫细胞和T细胞。阿尔法细胞出现 抵抗β细胞中Adar 1缺陷引起的Adar 1破坏或胰岛炎症。 我们建议：1）在RNA遗传破坏后表征小鼠和人胰岛细胞 编辑，通过敲除或敲低关键RNA编辑酶Adar 1; 2）检查 Adar 1缺乏对β和α细胞功能和活力以及胰岛的影响 炎症和自身免疫;和3）研究分化的分子基础 α和其他胰岛细胞类型对Adart1的依赖性。这项研究是一个结束 3个具有互补专业知识的团队合作：Al Powers（人类胰岛生物学 和功能），Yuval Dor（小鼠模型，分子生物学）和Erez Levanon（计算 RNA编辑分析）。这项工作将揭示RNA编辑的作用，这是一个关键 在胰岛细胞中的表位转录组修饰。它还将反驳或提供临床前支持， 有争议的假设，即有缺陷的RNA编辑可能有助于T1D的各个方面， 发病机制，特别是早期的抗病毒炎症反应。 1

RNA editing, a fundamental cellular process, involves the deamination of some adenosines in RNA to inosines, by the adenosine deaminases Adar1 (ADAR) and Adar2 (ADARB1). Recent studies have shown that a critical role of RNA editing is to disrupt double-stranded RNA (dsRNA) structures that are generated by retroelements inserted in the genome in an inverted orientation within expressed genes. The dsRNA formed by such sequence configurations is a powerful and dangerous activator of the ancient antiviral interferon response, which may lead to pathogenic inflammation. While RNA editing has been studied in the context of some organs and in cancer, very little is known about the role of ADAR enzymes in islet cell function and health. Our goal is to elucidate the role of RNA editing in islets, and particularly in alpha and beta cells. Strikingly, GWAS studies of type 1 diabetes (T1D) have revealed protective variants of IFIH1/MDA5, a cytosolic receptor that recognizes double-stranded RNA (dsRNA) from either viral or endogenous origins, and elicits an inflammatory response. Thus, defective RNA editing can in principle contribute to the islet anti-viral response which precedes autoimmunity. We hypothesize that impaired RNA editing and accumulation of endogenous dsRNA in beta cells trigger an IFIH1-dependent interferon response causing islet inflammation, which leads to beta cell dysfunction and potentially to autoimmunity. In our preliminary findings, we found that disruption of A-to-I RNA editing in adult mouse beta-cells in vivo or in human islets triggers an interferon response. In mice with Adar1-deficient beta cells, this leads to massive immune response localized to islets, including both innate immune cells and T cells. Alpha cells appear to resist Adar1 disruption or islet inflammation brought about by Adar1 deficiency in beta cells. We propose to 1) characterize mouse and human islet cells following genetic disruption of RNA editing, via knockout or knockdown of the key RNA editing enzyme Adar1; 2) examine the effects of Adar1 deficiency on beta and alpha cell function and viability, as well as islet inflammation and autoimmunity; and 3) investigate the molecular basis for the differential dependence of alpha and other islet cell types on Adart1. The proposed research is a close collaboration between 3 teams with complementary expertise: Al Powers (human islet biology and function), Yuval Dor (mouse models, molecular biology) and Erez Levanon (computational analysis of RNA editing). This work will shed light on the role of RNA editing, a key epitranscriptomic modification, in islet cells. It will also refute or provide pre-clinical support for the provocative hypothesis that defective RNA editing may contribute to aspects of T1D pathogenesis, particularly the early, anti-viral inflammatory response. 1