INTERMEDIARY METABOLISM IN THE BETA CELL AND NOVEL THERAPIES FOR NIDDM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 纽加德实验室使用跨学科方法研究葡萄糖刺激的胰岛素分泌所涉及的生化和分子机制，包括开发新的细胞模型、基因发现和基因工程。该计划项目赠款(PPG)的首要目标仍然是开发治疗2型糖尿病的新疗法。该计划从1999年作为德克萨斯大学达拉斯西南医学中心(UTSWMC)内三个研究中心之间的合作发展到目前的形式，包括位于UTSWMC的四个中心和杜克大学医学中心的合作。该计划将继续其独特的形式，将糖尿病机制项目与专注于研究和治疗这种疾病的新技术开发的项目融合在一起。在过去的供资周期中，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。项目1(Newgard)将研究先前资助时期出现的控制β细胞功能和生长的新途径，特别是同源结构域转录因子Nkx6.1在正常和功能失调的成熟胰岛细胞生物学中的作用。项目2(Sherry)致力于开发新的PET和MR试剂，用于活体胰岛β细胞的分子成像。项目3(Kodadek)将创造细胞可渗透的合成分子，能够激活胰岛β细胞中特定性能或生长促进基因的表达。这些项目将得到一个行政核心(核心A)、一个针对胰岛的核心(核心B)和一个代谢组学核心(核心C)的支持，前者部署了两项新技术，用于将分子货物运送到活体动物的胰岛β细胞，后者提供了基于最先进的质谱仪(MS)和核磁共振(核磁共振)的技术，用于全面的代谢图谱和新陈代谢通量测量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Newgard laboratory uses interdisciplinary approaches for the study of the biochemical and molecular mechanisms involved in glucose-stimulated insulin secretion, including development of novel cellular models, gene discovery and genetic engineering. The overarching goal of this program project grant (PPG) continues to be the development of novel therapies for type 2 diabetes. The program has evolved from its genesis in 1999 as a collaboration between three research Centers within the University of Texas Southwestern Medical Center in Dallas (UTSWMC) to its current format, involving collaboration of four Centers located at UTSWMC and Duke University Medical Center. The program will continue with its unique format of melding projects on diabetes mechanisms with projects focused on development of new technologies for studying and treating the disease. In the past funding cycle, the most compelling advances 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. Project 1 (Newgard) will investigate novel pathways for control of beta-cell function and growth that have emerged in the prior funding period, particularly the role of the homeodomain transcription factor Nkx6.1 in the biology of normal and dysfunctional mature islet cells. Project 2 (Sherry) seeks to develop novel PET and MR agents for molecular imaging of islet beta-cells in vivo. Project 3 (Kodadek) will create cell permeable synthetic molecules capable of activating the expression of specific performance- or growth-enhancing genes in islet beta-cells. These projects will be supported by an Administrative Core (Core A), an Islet Targeting Core (Core B), which deploys two novel technologies for delivery of molecular cargo to islet beta-cells in living animals, and a Metabolomics Core (Core C), which provides state-of-the-art mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based technologies for comprehensive metabolic profiling and measurement of metabolic flux.