Nkx6.1 REGULATION OF ISLET BIOLOGY

在这个项目项目赠款(PPG)的头五年里，我们的实验室一直在 应用跨学科方法确定肝、胰岛代谢异常 糖尿病和肥胖症中的β细胞和骨骼肌。在同一时间段内， 这个PPG团队已经开发了功能成像、基因靶向传递和 其他分子货物，以及定制的基因激活开关。最引人注目的进步 PPG团队已经在胰岛生物学和相关技术领域取得了进展。 因此，我们选择将此应用程序的竞争性续订重点放在开发新的 了解和逆转2型糖尿病患者β细胞功能障碍的策略。这样做的目的是 项目(项目1)是调查和验证控制β细胞功能和生长的新途径 这是我们在上一次供资期间的工作中产生的。该项目将广泛利用 在核心B中驻留的非凡技术用于成年动物的贝塔细胞特异性基因传递，以及在 核心C用于对胰岛和β细胞系进行全面的基于MS和核磁共振的代谢分析。这个 该项目的具体目标是：1)调查操纵 同源结构域转录因子Nkx6.1及其靶基因影响葡萄糖刺激的胰岛素 胰岛分泌(GSIS)；2)研究操纵 同源结构域转录因子Nkx6.1及其靶基因影响胰岛生长；3)检测 Nkx6.1及其靶基因在β细胞保存中的潜在保护或修复作用 2型糖尿病细胞和动物模型中的质量和功能。

Over the first five years of funding of this program project grant (PPG), our laboratory has been applying an interdisciplinary approach for defining metabolic abnormalities of liver, pancreatic islet beta-cells, and skeletal muscle in diabetes and obesity. Over the same time period, other members of this PPG team have developed technologies for functional imaging, targeted delivery of genes and other molecular cargo, and customized gene activation switches. The most compelling advances made by the PPG team have occurred in the area of pancreatic islet biology and related technologies. We have therefore chosen to focus the competitive renewal of this application on development of new strategies for understanding and reversing beta-cell dysfunction of type 2 diabetes. The goal of this project (Project 1) is to investigate and validate novel pathways for control of beta-cell function and growth that have emerged from our work in the prior funding period. The project will make extensive use of extraordinary technologies resident in Core B for beta-cell specific gene delivery in adult animals, and in Core C for comprehensive MS- and NMR-based metabolic analysis of islets and beta-cell lines. The specific aims of the project are: 1) To investigate mechanisms by which manipulation of the homeodomain transcription factor Nkx6.1 and its target genes affect glucose-stimulated insulin secretion (GSIS) in pancreatic islets; 2) To investigate mechanisms by which manipulation of the homeodomain transcription factor Nkx6.1 and its target genes affect pancreatic islet growth; 3) To test the potential protective or restorative effect of Nkx6.1 and its target genes in preservation of beta-cell mass and function in cellular and animal models of type 2 diabetes.