Integrative Metabolic Adaptations to Enviromental and Nutritional Challenge

简介（由申请人提供）：糖尿病是一种受复杂遗传和环境因素影响的多器官疾病。全面了解胰岛素抵抗和2型糖尿病（T2DM）需要一种综合的方法，研究不同细胞类型如何通过激素、神经和代谢信号相互影响，这些信号都是在机体外应激（包括营养过剩和正常昼夜节律中断）的背景下产生的。在本应用中提出的所有研究的目标是从分子角度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。该项目汇集了五位杰出的研究者，每一位都作为独立研究者取得了相当大的成功，但每一位都对科学合作的价值有着真正的信念。每个PI专注于一个特定的器官系统，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Project 1中，Lazar研究了抵抗素如何协调多器官对营养超载的反应，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着重研究了β细胞对外周应激的反应

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. PUBLIC HEALTH RELEVANCE: The proposed studies will address major and specific questions relevant to diabetes and metabolic diseases. At the same time, the specific investigators, environment, and format of this proposal facilitate interactions that should enhance the discovery process. There is an excellent likelihood that advances made by this program project group will have a positive impact on the epidemics of diabetes and metabolic diseases that are ravaging our society.