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B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B细胞功能障碍。这个项目(项目1)的目标是调查和验证控制B细胞功能和生长的新途径，这些途径是我们在前一个资助期的工作中出现的。该项目将广泛利用核心B中的非凡技术在成年动物中传递B细胞特异性基因，并在核心C中对胰岛和B细胞系进行全面的基于MS和核磁共振的代谢分析。该项目的具体目标是：1)研究操纵同源域转录因子Nkx6.1及其靶基因影响葡萄糖刺激的胰岛素的机制 2)研究同源结构域转录因子Nkx6.1及其靶基因影响胰岛生长的机制；3)检测Nkx6.1及其靶基因在细胞和2型糖尿病动物模型中对B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 B-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 B-cell dysfunction of type 2 diabetes. The goal of this project (Project 1) is to investigate and validate novel pathways for control of B-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 B-cell specific gene delivery in adult animals, and in Core C for comprehensive MS- and NMR-based metabolic analysis of islets and B-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 B-cell mass and function in cellular and animal models of type 2 diabetes .