Characterizing the role of novel long non coding RNA in diabetes onset and progression

在胰腺发育过程中，细胞接收并响应信号，这些信号将它们的决定导向特定的 血统在过去的几十年里，合作努力使我们获得了广泛的知识， 胰腺发育、胰岛组成和细胞命运规格和功能。此外，日益 人类胰腺样本的可用性使我们能够探索 人类和小鼠胰腺生物学。虽然这一重大进展提高了我们对 胰岛细胞生物学和糖尿病，我们仍然无法确定导致1型糖尿病的突变， 2型糖尿病，这表明我们缺少一些关键的监管机构。其中一个最重要的发现是， 基因组生物学是大部分基因组被转录并产生大量非编码RNA。 在生物学的大多数方面显示出重要的非编码RNA亚型之一是长非编码RNA。 RNA（lncRNA）的特征是缺乏蛋白质编码潜力，长度超过200 个核苷酸我们假设组织特异性lncRNA在特化细胞中发挥重要作用， 特异性功能，lncRNA的失调可能导致细胞功能障碍， 疾病，如糖尿病。我们已经鉴定了几种潜在的候选保守lncRNA， 在糖尿病期间表达变化。在本提案中，我们将重点关注lncRNA 6330403 K 07 Rik（633）， 以前未表征的lncRNA，在小鼠和人类中保守，其表达增加 在多种β细胞功能障碍的小鼠模型中显著。糖尿病受试者的人类GWAS研究 也鉴定了633人类直系同源物附近的SNP。我会评估表达谱和时间轴 633在db/db小鼠中2型糖尿病发作和进展期间的上调，并测试633的作用。 在体外和体内，在β细胞中过表达。此外，我将在糖尿病小鼠模型中删除633， 确定其对β细胞功能障碍的贡献程度。这个项目为我们提供了一个独特的 有机会了解lncRNA的上调如何影响糖尿病的发病和进展。的 提出的方法将使我能够确定参与糖尿病的重要分子机制 进展，并有可能开发关键的治疗靶点。

During pancreas development cells receive and respond to signals that direct their decisions towards specific lineages. In the past few decades collaborative efforts have allowed us to gain extensive knowledge about pancreas development, islet composition and cell fate specification and function. Furthermore the increasing availability of human pancreas samples have allowed us to explore the similarities and differences between human and mouse pancreas biology. Although this significant progress has improved our understanding of islet cell biology and diabetes we have still not been able to identify mutations that contribute to Type 1 and Type 2 diabetes, suggesting that we are missing some key regulators. One of the most significant findings in genome biology is that most of the genome is transcribed and produces a large variety of non-coding RNAs. One of the non-coding RNA subtypes shown to be important in most aspects of biology are the long noncoding RNAs (lncRNAs) that are characterized by their lack of protein coding potential and length of more than 200 nucleotides. We hypothesize that tissue specific lncRNAs play important roles in specialized cell- specific functions, and that dysregulation of lncRNAs might result in cellular dysfunctions to cause disorders, such as diabetes. We have identified several potential candidate conserved lncRNAs whose expression changes during diabetes. In this proposal we will focus on lncRNA 6330403K07Rik (633), a previously uncharacterized lncRNA that is conserved in mouse and humans, and whose expression increases significantly in multiple mouse models of beta cell dysfunction. Human GWAS studies on diabetic subjects have also identified SNPs in the vicinity of the 633 human ortholog. I will assess expression profile and timeline of 633 upregulation during Type 2 diabetes onset and progression in db/db mice and test the effects of 633 overexpression in beta cells, in vitro and in vivo. Additionally, I will delete 633 in a diabetic mouse model to determine the extent of its contribution to the beta cell dysfunction. This project provides us with a unique opportunity to understand how the upregulation of a lncRNA might impact diabetes onset and progression. The proposed approaches will allow me to identify important molecular mechanisms involved in diabetes progression and has the potential to develop crucial therapeutic targets.