Integrative Metabolic Adaptations to Enviromental and Nutritional Challenge

描述（由申请人提供）：糖尿病是一种多器官疾病，对复杂的遗传和环境因素有反应。完整了解胰岛素抵抗和2型糖尿病（T2DM）需要一种综合方法，即询问不同的细胞类型如何通过激素，神经和代谢信号相互影响，所有这些都是在机体外压力的背景下进行的，包括营养过剩和正常昼夜节律的破坏。本申请中提出的所有研究的目标是用分子术语解释正常和病理代谢，强调细胞自主过程以及依赖于有机体整合的过程。该计划项目汇集了五位杰出的研究人员，每一位都是独立研究者，过去取得了相当大的成功，但每一位都真正相信科学合作的价值。每个PI都专注于特定的器官系统以及它如何与其他组织和外部压力相互作用，并与研究相关问题的其他PI密切沟通。在项目1中，Lazar讨论了胰岛素如何协调多器官对营养过载的反应，其中炎症反应导致胰岛素靶组织和心血管系统的不良后果。在项目2中，Stoffers专注于β细胞对外周应激的反应。 胰岛素抵抗，测试一个有趣的模型，连接转录调控内质网生物合成和细胞生长。在项目3中，Ahima使用小鼠喂养夹带模型来模拟人类的昼夜节律中断，以研究中枢神经系统如何影响肝脏代谢。在项目4中，Kaestner还研究了对扰动的中央时钟的反应，但在激素环境如何影响肝脏葡萄糖代谢的转录控制的背景下。最后，在项目5中，Birnbaum还考虑了肝脏代谢对肥胖压力的反应，但也询问了抗糖尿病药物二甲双胍如何使其正常化。该项目由三个核心支持，提供组织化学分析，转基因小鼠的产生及其代谢表型。

DESCRIPTION (provided by applicant: Diabetes is a disease of multiple organs responding to complex genetic and environmental factors. A complete understanding of insulin resistance and type 2 diabetes mellitus (T2DM) requires an integrative approach that asks how different cell types influence each other through hormonal, neural, and metabolic signals all in the context of extra-organismal stresses including overnutrition and disruptions in normal circadian rhythms. A goal of all studies proposed in this application is to explain normal and pathological metabolism in molecular terms, emphasizing both cell autonomous processes as well as those that depend on organismal integration. The Program Project brings together five outstanding investigators, each with considerable past success as an independent investigator, but each also with a genuine belief in the value of scientific collaboration. Each PI focuses on a specific organ system and how it interacts with other tissues and external stresses, and works in close communication other PIs who study related problems. In Project 1, Lazar addresses how resistin coordinates the multi-organ response to nutritional overload, in which an inflammatory response leads to adverse consequences in insulin target tissues and the cardiovascular system. In Project 2, Stoffers focuses on the response of the beta cell to the stress of peripheral insulin resistance, testing an intriguing model that connects transcriptional regulation to endoplasmic reticulum biosynthesis and cell growth. In Project 3, Ahima uses a mouse feeding entrainment model that mimics circadian disruption in humans to examine how the central nervous system influences hepatic metabolism. In Project 4, Kaestner also studies the response to a perturbed central clock, but in the context of how the hormonal milieu influences the transcriptional control of liver glucose metabolism. Lastly, in Project 5, Birnbaum also considers how hepatic metabolism responds to the stress of obesity, but also asks how it is normalized by the antidiabetic drug metformin. The projects are supported by three Cores that provide histochemical analysis, generation of genetically modified mice, and their metabolic phenotyping.