Metabolic basis of beta cell stress adaptation

β细胞应激适应的代谢基础

• 批准号: 10339887
• 负责人: Feyza Engin
• 金额: $ 19.42万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339887
• 关键词: Address; Affect; Alteration in Respiration; Animal Model; Autoimmune; Beta Cell; Bioenergetics; Calcium Oscillations; Cell Respiration; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cellular Stress; Chemicals; Complement; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Down-Regulation; Energy Supply; Exhibits; Failure; Foundations; Genus Hippocampus; Glycolysis; Goals; Health; Homeostasis; Human; Image; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Leptin; Maintenance; Mediating; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Mus; Neurons; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oxidative Phosphorylation; Patients; Pharmacology; Play; Prevention; Process; Public Health; Publications; Recovery; Regimen; Regulation; Reporting; Respiration; Rodent Model; Role; Stress; Structure of beta Cell of islet; System; T memory cell; Testing; Therapeutic; Transmission Electron Microscopy; United States; Work; base; biological adaptation to stress; cell dedifferentiation; cost; experimental study; functional loss; functional restoration; fusion gene; human model; improved; inhibitor/antagonist; insight; islet; mouse model; novel therapeutic intervention; pre-clinical; preservation; response; sensor; stem cells; therapeutically effective; tool; transdifferentiation; treatment strategy

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β-cells and affects approximately 3 million people in the United States and 10–20 million worldwide. The rapidly increasing incidence of T1D, as much as 3-5% per year, is of great concern. Although autoimmune-mediated β-cell destruction is the major cause of T1D, emerging data suggest that intrinsic β-cell stress, defective adaptive stress responses, and β-cell dedifferentiation can contribute to the loss of functional β-cell mass not only in T2D, but also in T1D. Despite these intriguing findings, mechanisms by which β-cells recover from stress and restore their function and identity remain largely unknown, and there is an urgent need to address this critical gap in knowledge to improve the therapeutic options of patients with diabetes. We recently reported that deletion of the key stress response sensor, IRE1α, in β-cells of non-obese diabetes (NOD) mice (IRE1αβ-/-), leads to transient β-cell dedifferentiation. Interestingly, these mice recover from stress and are protected from T1D. IRE1αβ-/- mice serve as an excellent model to study how β-cells adapt to stress and restore their identity and function under stress conditions. Ample data show that cellular stress triggers numerous adaptive responses, including metabolic rewiring. Consistent with this observation, our preliminary data obtained from this model showed significant alterations in metabolism and mitochondrial morphology. Based on our preliminary data, we hypothesize that stress adaptation in β-cells is governed by metabolic reprogramming and mitochondrial remodeling. To test this hypothesis, we propose the following specific aims: Aim 1: Identify the temporal dynamics and regulation of mitochondrial processes and bioenergetics in β-cells of IRE1αβ-/- mice: (1) Through imaging, and metabolic flux analyses at different states of differentiation, we will examine mitochondrial respiration and fusion, and (2) unravel the regulation of key fusion genes and the activity of the master regulator of respiration in β-cells of IRE1αβ-/-. Aim 2: Determine the role of metabolic reprogramming and mitochondrial remodeling in identity, function, and stress recovery of β-cells of IRE1αβ-/- mice. We will genetically and pharmacologically (1) alter the metabolic state in stressed islets from T1D animal models, (2) modulate the mitochondrial dynamics in stressed β-cells of IRE1αβ-/- mice ex vivo, and then examine β-cell function, identity, and survival in these systems. Aim 3: Elucidate the effects of metabolic alterations on β- cell redifferentiation and function in a mouse model of T2D and human islets. To complement our studies with the NOD model, we will perform the experiments from Aim 2, in β-cells of leptin-deficient obese ob/ob mice (a model of T2D), and in islets from T2D donors. This work will define the role of oxidative metabolism and mitochondrial dynamics in stress adaptation, maintenance of β-cell identity and function, significantly impact our understanding of mechanisms of β-cell failure and will provide insight into development of novel therapeutic strategies for the treatment of both T1D and T2D.

项目摘要/摘要 1型糖尿病（T1D）由自身免疫介导的胰腺β细胞破坏并影响 在美国，大约有300万人和全球100亿人。迅速增加 T1D的发病率每年高达3-5％，令人关注。虽然自身免疫性介导的β细胞 破坏是T1D的主要原因，新出现的数据表明固有的β细胞应力，有缺陷的适应性应力 反应和β细胞去分化可能导致功能性β细胞质量的丧失，不仅在T2D中，而且会导致 也在T1D中。尽管有这些有趣的发现，但β细胞从压力中恢复并恢复其的机制 功能和身份在很大程度上仍然未知，迫切需要解决这一关键差距 知识以改善糖尿病患者的治疗选择。我们最近报告了删除 非肥胖糖尿病（NOD）小鼠（IRE1αβ-/ - ）的β细胞中的关键应力反应传感器IRE1α导致 瞬态β细胞去分化。有趣的是，这些小鼠从压力中恢复并受到T1D的保护。 IRE1αβ-/ - 小鼠是研究β细胞如何适应压力和恢复其身份的出色模型 在压力条件下的功能。大量数据表明，细胞应力会触发许多自适应反应， 包括代谢重新布线。与此观察结果一致，我们从该模型获得的初步数据 显示新陈代谢和线粒体形态的显着改变。根据我们的初步数据，我们 假设β细胞中的应力适应受代谢重编程和线粒体的控制 重塑。为了检验这一假设，我们提出以下特定目的：目标1：确定临时性 IRE1αβ-/ - 小鼠的线粒体过程的动力学和调节：（1） 通过成像和不同分化状态的代谢通量分析，我们将检查 线粒体呼吸和融合，以及（2）阐明关键融合基因的调节和活性 IRE1αβ-/ - 的β细胞中呼吸的主调节剂。目标2：确定代谢重编程的作用 以及IRE1αβ-/ - 小鼠的β细胞的身份，功能和应力恢复中的线粒体重塑。我们 将一般和药物（1）在T1D动物模型的压力胰岛中改变代谢状态， （2）调节IRE1αβ-/ - 小鼠的应力β细胞的线粒体动力学，然后检查β细胞 这些系统的功能，身份和生存。目标3：阐明代谢改变对β-的影响 细胞在T2D和人类胰岛的小鼠模型中重新分化和功能。完成我们的学习 使用点头模型，我们将在瘦素缺乏肥胖的肥胖ob/ob小鼠的β细胞中执行AIM 2的实验 （T2D的模型），以及T2D捐赠者的胰岛。这项工作将定义氧化代谢和 应力适应，维持β细胞身份和功能的线粒体动力学，显着影响 我们对β细胞衰竭机制的理解，并将为新颖的发展提供洞察力 治疗T1D和T2D的治疗策略。