Nkx6.1 REGULATION OF ISLET BIOLOGY

在这个项目资助(PPG)的头五年里，我们的实验室一直在应用跨学科的方法来定义糖尿病和肥胖症患者的肝脏、胰岛β细胞和骨骼肌的代谢异常。在同一时期，PPG团队的其他成员开发了功能成像、基因和其他分子货物的靶向传递以及定制的基因激活开关等技术。PPG团队取得的最引人注目的进展出现在胰岛生物学和相关技术领域。 因此，我们选择将这一应用的竞争性更新集中于开发新的策略，以了解和逆转2型糖尿病的β细胞功能障碍。这个项目(项目1)的目标是调查和验证我们在前一个资助期的工作中出现的控制β细胞功能和生长的新途径。该项目将广泛使用核心B中的非凡技术用于成年动物的β细胞特异性基因传递，以及核心C中基于MS和核磁共振的全面胰岛和β细胞系代谢分析。这个 该项目的具体目标是：1)调查操纵 目的：1)研究同源结构域转录因子Nkx6.1及其靶基因对胰岛葡萄糖刺激的胰岛素分泌(GSIS)的影响；2)研究同源结构域转录因子Nkx6.1及其靶基因对胰岛生长的影响机制；3)检测Nkx6.1及其靶基因在2型糖尿病细胞和动物模型中对胰岛β细胞质量和功能的保护或修复作用。

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.