Nkx6.1 Regulation of Islet Biology

Nkx6.1 胰岛生物学的调节

• 批准号: 8147685
• 负责人: CHRISTOPHER B NEWGARD
• 金额: $ 8.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147685
• 关键词: Affect; Animal Model; Area; B-Lymphocytes; Biological Preservation; Biology; Cell Line; Cell physiology; Development; Diabetes Mellitus; Functional Imaging; Functional disorder; Funding; Gene Activation; Gene Delivery; Gene Targeting; Genes; Glucose; Goals; Growth; Islets of Langerhans; Laboratories; Liver; Metabolic; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Program Research Project Grants; Regulation; Skeletal Muscle; Technology; Testing; Time; Work; base; homeodomain; insulin secretion; interdisciplinary approach; islet; mature animal; member; novel; targeted delivery; transcription factor

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 .

在该计划项目拨款 (PPG) 资助的前五年中，我们的实验室一直在应用跨学科方法来定义糖尿病和肥胖症中肝脏、胰岛 B 细胞和骨骼肌的代谢异常。同一时期，该 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递送以及定制基因激活开关的技术。 PPG 团队取得的最引人注目的进展发生在胰岛生物学和相关技术领域。 因此，我们选择将该应用程序的竞争性更新重点放在开发新策略上，以了解和逆转 2 型糖尿病的 B 细胞功能障碍。该项目（项目 1）的目标是研究和验证我们在之前资助期间的工作中发现的控制 B 细胞功能和生长的新途径。该项目将广泛利用 Core B 中的非凡技术在成年动物中进行 B 细胞特异性基因传递，以及 Core C 中的非凡技术对胰岛和 B 细胞系进行基于 MS 和 NMR 的全面代谢分析。该项目的具体目标是： 1) 研究同源域转录因子 Nkx6.1 及其靶基因的操纵影响葡萄糖刺激的胰岛素的机​​制 胰岛的分泌（GSIS）； 2) 研究同源域转录因子Nkx6.1及其靶基因的操作影响胰岛生长的机制； 3) 测试Nkx6.1及其靶基因在2型糖尿病细胞和动物模型中保存B细胞质量和功能的潜在保护或恢复作用 。