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

基本信息

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
项目类别：
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

项目摘要

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.

在过去的几次几十年。 1型糖尿病是β细胞死亡的结果，或胰腺中产生胰岛素细胞的凋亡。虽然有多种已知的β细胞凋亡触发因素，但大多数进食途径会导致β细胞中活性氧（ROS）的产生增加。未检查的β细胞ROS的积累会破坏细胞稳态，导致氧化损伤并导致凋亡。对ROS增加的典型自适应反应包括转录因子NRF2的激活，该因子刺激细胞保护抗氧化剂反应并恢复稳态。我们最近发现，在β细胞夫妇自噬对抗氧化剂反应的自噬中，白介素-6（IL-6）受体信号传导和NRF2的串联激活，减少β细胞ROS和预防氧化损伤以增加体内β细胞存活。重要的是，我们发现NRF2在线粒体中的非传统作用与线粒体的刺激，即通过自噬对线粒体的选择性降解。总的来说，这些数据导致了我们的假设，即自噬和抗氧化剂反应在β细胞中耦合，并且这些过程的编排对于维持β细胞稳态和预防糖尿病至关重要。拟议的工作将使用培养的胰岛/β细胞和小鼠的体内分析融合体外实验。我们将追求以下特定目的：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/抗氧化剂响应耦合； 2）确定自噬/抗氧化剂反应与β细胞稳态的体内贡献。总体而言，这些实验将定义自噬/抗氧化反应耦合在对压力的自适应反应中的作用，并使我们能够在已知导致β细胞衰竭的条件下确定引导胰岛内信号事件的治疗靶标。我在印第安纳州糖尿病和代谢疾病中心内的β细胞生物学和资源背景使我非常适合实现该项目的目标。