Project 1: Nkx6.1 REGULATION OF ISLET BIOLOGY

在该计划项目资助（PPG）的前五年，我们的实验室已经 应用跨学科方法定义肝、胰岛、 β-细胞和骨骼肌在糖尿病和肥胖症。在同一时期， 这个PPG团队已经开发了功能成像技术，基因的靶向递送， 其他分子货物和定制的基因激活开关。最引人注目的进步 PPG团队在胰岛生物学和相关技术领域取得的进展。 因此，我们选择将此应用程序的竞争性续订集中在新的 了解和逆转2型糖尿病β细胞功能障碍的策略。这个目标 一个项目（项目1）是研究和验证控制β细胞功能和生长的新途径 我们在上一个供资期的工作中发现的问题。该项目将广泛利用 核心B中用于成年动物β细胞特异性基因递送的非凡技术，以及 Core C用于胰岛和β细胞系的全面MS和NMR代谢分析。的 该项目的具体目标是：1）调查操纵 同源域转录因子Nkx6.1及其靶基因对葡萄糖刺激胰岛素的影响 胰岛分泌（GSIS）; 2）研究操纵GSIS的机制， 同源域转录因子Nkx6.1及其靶基因对胰岛生长的影响 Nkx6.1及其靶基因在β细胞保存中潜在保护或恢复作用 在2型糖尿病的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.