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 .

在该计划项目赠款（PPG）的前五年中，我们的实验室一直在采用跨学科方法来定义肝脏和肥胖症中肝脏B细胞的代谢异常，胰岛B细胞和骨骼肌。在同一时期，该PPG团队的其他成员开发了用于功能成像，基因和其他分子货物的靶向输送以及定制基因激活开关的技术。 PPG团队最引人注目的进步发生在胰岛生物学和相关技术领域。 因此，我们选择将本应用的竞争性更新集中在理解和逆转2型糖尿病的B细胞功能障碍的新策略上。该项目的目的（项目1）是调查并验证新的途径来控制B细胞功能和增长，这些功能和增长从前的资金期间出现了。该项目将广泛使用核心B中的非凡技术，用于成人动物中B细胞特异性基因的递送，以及在核心C中进行全面的基于MS和NMR的胰岛和B细胞线的代谢分析。该项目的具体目的是：1）研究同源域转录因子NKX6.1及其靶基因对葡萄糖刺激的胰岛素的操纵的机制 胰岛的分泌物（GSI）； 2）研究了同源域转录因子NKX6.1及其靶基因影响胰岛生长的机制； 3）测试NKX6.1及其靶基因在保存B细胞质量以及在2型糖尿病的细胞和动物模型中的功能中的潜在保护或恢复作用 。