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.

项目总结/摘要 1型糖尿病（T1 D）是由自身免疫介导的胰腺β细胞破坏引起的， 美国约有300万人，全球约有1000万至2000万人。迅速增加的 每年高达3-5% T1 D的发病率是非常令人关注的。虽然自身免疫介导的β细胞 破坏是T1 D的主要原因，新的数据表明，内在的β细胞应激，缺陷的适应性应激， 反应，β细胞去分化不仅可以导致T2 D中功能性β细胞群的丧失， 在T1 D。尽管有这些有趣的发现，β细胞从压力中恢复并恢复其功能的机制仍然存在。 功能和特性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。我们最近报告说，删除 非肥胖糖尿病（NOD）小鼠（IRE 1 αβ-/-）β细胞中的关键应激反应传感器IRE 1 α导致 瞬时β细胞去分化。有趣的是，这些小鼠从压力中恢复，并受到T1 D的保护。 IRE 1 αβ-/-小鼠是研究β细胞如何适应压力并恢复其特性的极好模型， 在压力条件下发挥作用。充足的数据表明，细胞应激会引发许多适应性反应， 包括代谢重组与这一观察相一致，我们从这个模型中获得的初步数据 在代谢和线粒体形态上显示出显著的改变。根据初步数据，我们 假设β细胞中应激适应受代谢重编程和线粒体 重塑为了验证这一假设，我们提出了以下具体目标：目标1：确定时间 IRE 1 αβ-/-小鼠β细胞中线粒体过程和生物能量学的动力学和调节：（1） 通过成像和不同分化状态下的代谢通量分析，我们将研究 线粒体呼吸和融合，以及（2）解开关键融合基因的调控和线粒体呼吸和融合的活性。 IRE 1 αβ-/-β细胞中呼吸的主要调节因子。目的2：确定代谢重编程的作用 IRE 1 αβ-/-小鼠β细胞的身份、功能和应激恢复中的线粒体重塑。我们 将遗传地和间接地（1）改变来自T1 D动物模型的应激胰岛中的代谢状态， (2)调节离体IRE 1 αβ-/-小鼠应激β细胞中的线粒体动力学，然后检查β细胞 在这些系统中的功能、身份和生存。目的3：阐明代谢改变对β- T2 D小鼠模型和人胰岛中的细胞再分化和功能。为了补充我们的研究 在NOD模型中，我们将在瘦素缺乏的肥胖ob/ob小鼠的β细胞中进行目标2的实验 （T2 D模型）和来自T2 D供体的胰岛中。这项工作将确定氧化代谢的作用， 线粒体动力学在应激适应、维持β细胞身份和功能方面， 我们对β细胞衰竭机制的理解，将为开发新的 治疗T1 D和T2 D的治疗策略。