Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation

胰腺β细胞稳态调节中的自噬/抗氧化反应耦合

• 批准号: 10371254
• 负责人: Amelia K Linnemann
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371254
• 关键词: Adaptive Immune System; Affect; Antigens; Antioxidants; Apoptosis; Autoimmune Diabetes; Autoimmunity; Autophagocytosis; Autopsy; B-Cell Activation; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Beta Cell; Cell Death; Cell Survival; Cells; Cellular biology; Cessation of life; Chemicals; Communication; Coupled; Couples; Coupling; Data; Development; Diabetes Mellitus; Diabetes prevention; Drug Delivery Systems; Etiology; Event; Excision; Exogenous Factors; Failure; Functional disorder; Future; GLP-I receptor; Generations; Genetic Transcription; Glucose; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; In Situ; In Vitro; Incidence; Indiana; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 6 Receptor; Interleukin Activation; International; Intervention; Laboratories; Lead; Link; Maintenance; Mediating; Metabolic Diseases; Methods; Mitochondria; Molecular; Morbidity - disease rate; Mus; Nature; Organelles; Pancreas; Pathway interactions; Play; Population; Prediabetes syndrome; Predisposition; Process; Proteins; Proteomics; Reactive Oxygen Species; Receptor Signaling; Recycling; Regulation; Reporting; Research; Resources; Role; Secretory Cell; Signal Pathway; Signal Transduction; Streptozocin; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Transcriptional Activation; Tumor-infiltrating immune cells; United States; Work; autoimmune pathogenesis; base; cost estimate; cytokine; diabetes pathogenesis; diabetogenic; disorder prevention; experimental study; extracellular; in vivo; insulin secretion; intravital microscopy; islet; mitochondrial autophagy; mouse model; nanoparticle; new therapeutic target; novel; oxidative damage; preservation; response; restoration; therapeutic target; transcription factor; translational potential

The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Type 1 diabetes is a result of β-cell death, or apoptosis of the insulin-producing cells in the pancreas. While there are a variety of known triggers for β-cell apoptosis, most feed into pathways that lead to increased generation of reactive oxygen species (ROS) in the β-cell. Unchecked accumulation of β-cell ROS can disrupt cellular homeostasis, cause oxidative damage, and lead to apoptosis. A typical adaptive response to increased ROS includes activation of the transcription factor NRF2, which stimulates the cell-protective antioxidant response and restores homeostasis. We recently found that tandem activation of interleukin-6 (IL-6) receptor signaling and NRF2 in the β-cell couples autophagy to the antioxidant response, reduces β-cell ROS, and protects against oxidative damage to increase β-cell survival in vivo. Importantly, we discovered that non-canonical actions of NRF2 in the mitochondria were associated with the stimulation of mitophagy, the selective degradation of mitochondria by autophagy. Collectively, these data lead to our hypothesis that autophagy and antioxidant response are coupled in the β-cell and that orchestration of these processes is essential for maintenance of β-cell homeostasis and diabetes prevention. The proposed work will incorporate both in vitro experiments using cultured islets/ β-cells and in vivo analyses in mice. We will pursue the following specific aims: 1) To identify the mechanism controlling NRF2 mitochondrial translocation and determine its role in β-cell autophagy/antioxidant response coupling; and 2) To determine the in vivo contributions of autophagy/antioxidant response coupling to β-cell homeostasis. Overall, these experiments will define the role of autophagy/antioxidant response coupling in the adaptive response to stress and allow us to identify therapeutic targets guiding the signaling events within the islet under conditions known to lead to β-cell failure. My background in β-cell biology and resources within the Indiana Center for Diabetes and Metabolic Diseases makes me uniquely suited to accomplish the aims of this project.

在过去的几年里，美国人口中的糖尿病发病率一直在迅速增加 几十年。1型糖尿病是β细胞死亡的结果，也就是胰腺中产生胰岛素的细胞的凋亡。虽然β细胞的凋亡有多种已知的触发因素，但大多数都参与了导致β细胞中活性氧物种(ROS)生成增加的途径。β细胞内ROS的无节制积聚可破坏细胞内稳态，引起氧化损伤，并导致细胞凋亡。对ROS增加的典型适应性反应包括转录因子NRF2的激活，该转录因子刺激细胞保护性抗氧化反应并恢复体内平衡。我们最近发现，在β细胞中，白介素6(IL-6)受体信号和NRF2的串联激活耦合了对抗氧化反应的自噬，降低了β细胞的ROS，并 防止氧化损伤，提高体内β细胞的存活率。重要的是，我们发现NRF2在线粒体中的非规范作用与刺激有丝分裂，即通过自噬选择性地降解线粒体有关。总而言之，这些数据导致了我们的假设，即自噬和抗氧化反应在β细胞中是耦合的，这些过程的协调对于维持β细胞的动态平衡和预防糖尿病至关重要。这项拟议的工作将包括使用培养的胰岛/β细胞进行的体外实验和在小鼠身上的体内分析。我们将追求以下具体目标：1)确定控制NRF2线粒体易位的机制，并确定其在β-细胞中的作用 自噬/抗氧化反应偶联；以及2)确定自噬/抗氧化反应偶联在体内对β细胞稳态的贡献。总体而言，这些实验将确定自噬/抗氧化反应偶联在适应应激反应中的作用，并使我们能够识别在已知导致β细胞衰竭的条件下引导胰岛内信号事件的治疗靶点。我在β细胞生物学和印第安纳糖尿病和新陈代谢疾病中心的资源方面的背景使我非常适合完成这个项目的目标。