Functionalizing a T1D/T2D-associated locus within an intron of GLIS3.

项目总结 自古以来就有糖尿病的特征，这一组人的第一份文献记载了 可追溯到公元前1500年的疾病。虽然该领域在治疗方面取得了许多进展， 目前仍没有治愈糖尿病的方法。这对个人和个人都变得越来越成问题 整个医疗系统，因为糖尿病的发病率持续上升。据估计，为有疾病的个人提供的医疗保健 仅在美国，糖尿病每年造成的损失就超过2000亿美元。降低这些成本并改进 患者的治疗选择只是糖尿病相关研究如此关键的众多原因中的一小部分。 我将使用遗传学方法来更全面地了解糖尿病的发生和发展。在这 应用程序中，我重点介绍了一种集成人类和小鼠数据集的方法，以检查基因内和 基因组内含子区域与糖尿病易感性。一个这样的兴趣点位于第一内含子 GLIS3基因，并具有与1型糖尿病(T1D)和2型糖尿病相关的高度显著的SNPs (T2D)。为了研究这个Glis3T1D/T2D基因座，我们测定了小鼠的共线区，并删除了1729bp以创建 一种新的小鼠模型(GLIS31729小鼠)。我发现这些小鼠表现出高血糖，尽管胰岛素增加了 分泌和葡萄糖引起的钙振荡。我这项提议的总体目标是使这一场所发挥作用 以努力阐明它在推动糖尿病中的作用。我对这个轨迹功能的中心假设是，它 在胰岛中作为GLIS3的增强子，基因座中与T1D/T2D相关的SNPs改变其活性。我要测试一下 这一假设，从而通过追求以下目的来实现本提案的目标：1)评估 Glis3T1D/T2D基因座的增强子活性，2)鉴定与T1D/T2D相关的SNPs对转录的影响 Glis3T1D/T2D基因座的因子结合，以及3)评估GLIS31729小鼠的差异表达(DE)基因 揭示Glis3T1D/T2D基因座在改变T1D和T2D风险中的作用。随着这些目标的实现，我 预期对这个非编码基因有更完整的了解，包括它如何调节基因表达 对1型和2型糖尿病的易感性都有影响。此外，我相信这项建议将提供 对我进行必要的培训，让我成为一名胰岛生物学家，并为我在一项研究中的终身教职做好准备 机构。

PROJECT SUMMARY Diabetes mellitus has been characterized since antiquity, with the first documentation of this group of disorders dating back to 1500 BC1. While many advances have been made in the field in terms of treatment, there remains no cure for diabetes. This has become increasingly problematic for both the individuals and the entire healthcare system as rates of diabetes continue to rise. It is estimated that healthcare for individuals with diabetes costs over $200 billion per year in the United States alone2. Diminishing these costs and improving treatment options for patients are just a couple of the many reasons why diabetes-related research is so critical. I will use a genetic approach to more fully understand the initiation and progression of diabetes. In this application, I highlight a method that integrates human and mouse datasets to examine the role of intragenic and intronic regions of the genome in diabetes susceptibility. One such locus of interest resides in the first intron of the GLIS3 gene and has highly significant SNPs associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D). To study this Glis3T1D/T2D locus, we determined the syntenic region in mouse and deleted 1729bp to create a novel mouse model (Glis31729 mouse). I found that these mice exhibit hyperglycemia, despite increased insulin secretion and glucose-evoked Ca2+ oscillations. My overall objective for this proposal is to functionalize this locus in an effort to elucidate its role in driving diabetes. My central hypothesis for the function of this locus is that it acts as an enhancer for Glis3 in islets, and that T1D/T2D-related SNPs within the locus alter its activity. I will test this hypothesis, and thus accomplish the goals of this proposal, by pursuing the following aims: 1) evaluate the enhancer activity of the Glis3T1D/T2D locus, 2) identify the influence of T1D/T2D-associated SNPs on transcription factor binding at the Glis3T1D/T2D locus, and 3) evaluate differentially expressed (DE) genes in the Glis3 1729 mice to reveal the role of the Glis3T1D/T2D locus on altering T1D and T2D risk. With the completion of these aims, I anticipate a more complete understanding of this non-coding locus, including how it regulates gene expression and affects both type 1 and type 2 diabetes susceptibility. Additionally, I believe this proposal will provide the necessary training for me to progress as an islet biologist and prepare me for a tenure-track position at a research institution.