Mechanisms and Targeted Control of Pancreatic B-Cell Antioxidant Response

胰腺 B 细胞抗氧化反应的机制和靶向控制

• 批准号: 10614991
• 负责人: Alissa N Novak
• 金额: $ 3.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614991
• 关键词: Advisory Committees; Affect; Antioxidants; Antisense Oligonucleotides; Arachidonate 15-Lipoxygenase; Autoimmune Diabetes; Autoimmune Diseases; Autopsy; Award; Beta Cell; Blood Glucose; Cell Death; Cell Survival; Cell physiology; Cells; Cytoprotection; DNA; Data; Deterioration; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Environment; Environmental Risk Factor; Functional disorder; Funding; Future; GCG gene; Generations; Genomics; Goals; Grant; Homeostasis; Hydrophobicity; Immune; Immune Tolerance; Immune response; Inbred NOD Mice; Indiana; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Maintenance; Mediating; Mentors; Metabolic; Metabolic Diseases; Micelles; Monitor; Onset of illness; Oral; Organelles; Oxidation-Reduction; Oxidative Stress; Pancreas; Pathway interactions; Persons; Pharmacodynamics; Polymers; Population; Predisposition; Preparation; Prevalence; Prevention; Problem Solving; Production; Proteins; Proteomics; Public Health; Reactive Oxygen Species; Repression; Research; Research Personnel; Residual state; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Stress; Structure of beta Cell of islet; Susceptibility Gene; Techniques; Testing; Therapeutic; Training; United States; United States National Institutes of Health; Universities; Work; Writing; alpha Tocopherol; autoimmune pathogenesis; career; design; diabetes pathogenesis; diabetogenic; experimental study; functional loss; glucagon-like peptide 1; imaging probe; immune cell infiltrate; immunogenicity; in vivo; islet; knock-down; medical schools; mouse model; nanoparticle; nanosized; new therapeutic target; novel; novel therapeutic intervention; oxidative damage; prevent; resilience; response; stressor; targeted imaging; targeted treatment; tool

PROJECT SUMMARY Type 1 Diabetes (T1D) is an autoimmune disease caused by progressive destruction of the insulin producing β- cells. The loss of immune tolerance is a result of predisposing genes and environmental factors. However, the exact trigger of autoimmune attack is currently not understood. During the development and progression of T1D, β-cell oxidative stress is a key contributing factor to β-cell dysfunction and destruction. For many years it was thought that β-cells were completely destroyed in individuals with T1D. Recently, this dogma has been challenged by the observation of residual insulin positive β-cells in individuals with long-standing T1D. Similarly, in the nonobese diabetic (NOD) mouse model for T1D, there is a subpopulation of β-cells that are able to withstand prolonged immune attack. These data suggest there is a population of β-cells that are able to adapt and survive during conditions of high stress. To build on these findings, the central goal of this proposal is to define pathways to promote β-cell survival and protection against T1D. I hypothesize that rapid activation of the antioxidant response reduces β-cell ROS to repress islet immunogenicity during T1D pathogenesis. I will test this hypothesis through two specific aims. Experiments in aim 1, will investigate how β-cell selective loss of NRF2 contributes to the development of autoimmune diabetes. In aim 2, I will identify the mechanism controlling β-cell ROS mitigation in early T1D pathogenesis. Completion of these aims will determine the functional role and mechanism of β-cell adaptive redox response in vivo. Importantly, this work will identify novel targets to prevent β-cell destruction under diabetogenic conditions, and tools developed and tested as a part of this work can be used in future studies to target therapeutics or imaging probes to the β-cells. These studies will also positively impact my career. Both a comprehensive understanding of islet function in early diabetes pathogenesis and the use of cutting-edge techniques will enable me to develop as a scientist and set me on a trajectory to make real and lasting impacts in the field of diabetes research. This F31 award entails a 2-year training plan designed to achieve 4 main objectives: 1) build a strong understanding of techniques and concepts in diabetes research, 2) train in the generation and use of targeted nanoparticles and pharmacodynamics for diabetes research, 3) train in oral and written presentation of research findings, including grant preparation, and 4) train in the use and handling of mouse models for diabetes research. In addition, the applicant will benefit from the outstanding and collaborative research environment provided by the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine. Her training will also benefit from a mentoring and advisory committee consisting of a diverse team of carefully selected and established NIH funded investigators. In summary, the proposed studies and training objectives will provide the applicant with a fertile training environment in which she can become a versatile independent researcher and develop an understanding of β-cell physiology.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，由产生胰岛素的β- 细胞免疫耐受性的丧失是易感基因和环境因素的结果。但 目前尚不清楚自身免疫性攻击的确切触发因素。在T1 D的发展和进展过程中， β细胞氧化应激是β细胞功能障碍和破坏的关键促成因素。多年来， 认为β细胞在T1 D患者中被完全破坏。最近，这一教条被 在长期T1 D患者中观察到残留的胰岛素阳性β细胞，这一点受到了挑战。同样地， 在T1 D的非肥胖糖尿病（NOD）小鼠模型中，有一个β细胞亚群能够 抵抗长期的免疫攻击这些数据表明有一群β细胞能够适应 并能在高压力下生存。在这些调查结果的基础上，本提案的中心目标是 定义促进β细胞存活和保护免受T1 D的途径。我推测，快速激活的 抗氧化反应减少β细胞ROS，抑制T1 D发病过程中的胰岛免疫原性。我将测试 这一假设通过两个具体的目标。目的1中的实验将研究β细胞如何选择性丧失 NRF 2有助于自身免疫性糖尿病的发展。在目标2中，我将确定控制 T1 D早期发病机制中的β细胞ROS缓解。这些目标的完成将决定其职能作用， 体内β细胞适应性氧化还原反应的机制。重要的是，这项工作将确定新的目标，以防止 在糖尿病条件下的β细胞破坏，以及作为这项工作的一部分开发和测试的工具， 在未来的研究中用于将治疗剂或成像探针靶向β细胞。这些研究也将积极 影响我的职业生涯。全面了解胰岛功能在糖尿病早期发病机制中的作用， 使用尖端技术将使我能够发展成为一名科学家，并使我走上一条使真实的 在糖尿病研究领域产生了深远的影响。该F31奖项需要一个为期2年的培训计划，旨在 实现4个主要目标：1）建立对糖尿病研究技术和概念的深刻理解，2） 培训靶向纳米颗粒的产生和使用以及糖尿病研究的药效学，3）培训 口头和书面介绍研究成果，包括准备补助金，以及4）培训使用和 处理糖尿病研究的小鼠模型。此外，申请人将受益于未完成的和 由印第安纳州糖尿病和代谢疾病中心提供的合作研究环境 大学医学院。她的培训还将受益于一个指导和咨询委员会， 一个由经过精心挑选和建立的NIH资助的研究人员组成的多元化团队。总之，拟议的 研究和培训目标将为申请人提供一个肥沃的培训环境， 成为一个多才多艺的独立研究人员，并发展β细胞生理学的理解。