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（T1D）是一种自身免疫性疾病，是由于胰岛素产生β-的进行性破坏引起的 细胞。免疫耐受性的丧失是易感基因和环境因素的结果。但是， 当前尚不清楚自身免疫攻击的确切触发因素。在T1D的发展和发展过程中， β细胞氧化应激是导致β细胞功能障碍和破坏的关键因素。多年来一直是 认为T1D的个体完全破坏了β细胞。最近，这个教条一直是 在长期存在T1D的个体中观察残留的胰岛素阳性β细胞的挑战。相似地， 在用于T1D的非肥胖糖尿病（NOD）小鼠模型中，β细胞的亚群可以 承受长时间的免疫进攻。这些数据表明有能够适应的β细胞人群 并在高压力条件下生存。在这些发现的基础上，该提议的核心目标是 定义促进β细胞存活和保护T1D的途径。我假设快速激活 在T1D发病机理期间，抗氧化剂反应减少了β细胞ROS以抑制胰岛免疫原性。我会测试 通过两个具体目标这一假设。 AIM 1中的实验将研究β细胞的选择性丢失 NRF2有助于自身免疫性糖尿病的发展。在AIM 2中，我将确定控制机制 早期T1D发病机理中的β细胞ROS减轻。这些目标的完成将决定功能作用，并且 体内β细胞自适应氧化还原反应的机理。重要的是，这项工作将确定新的目标以防止 在糖尿病生成状况下的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可以是 将来的研究用于靶向治疗或成像问题的β细胞。这些研究也将积极 影响我的职业。对早期糖尿病发病机理中胰岛功能的全面了解和 使用尖端技术将使我能够发展为科学家，并让我踏上轨迹，使我变得真实 以及糖尿病研究领域的持久影响。该F31颁奖典礼是一项为期两年的培训计划 实现4个主要目标：1）对糖尿病研究中的技术和概念建立深刻的了解，2） 训练有针对性的纳米颗粒和用于糖尿病研究的药效学的生成和使用，3）训练 在研究结果的口头和书面介绍中，包括赠款准备，4）在使用中训练 处理糖尿病研究的小鼠模型。此外，申请人将受益于未偿还和 印第安纳州糖尿病和代谢疾病中心提供的协作研究环境 大学医学院。她的培训还将从一个心理和咨询委员会中受益 由精心挑选和建立的NIH资助的调查人员组成的多元化团队。总而言之 研究和培训目标将为申请人提供肥沃的培训环境 成为一名多功能独立研究人员，并发展对β细胞生理的理解。