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.

项目概要 1 型糖尿病 (T1D) 是一种自身免疫性疾病，由产生胰岛素的β-胰岛素进行性破坏引起。 细胞。免疫耐受性的丧失是诱发基因和环境因素的结果。然而， 目前尚不清楚自身免疫攻击的确切触发因素。在 T1D 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因素。多年来一直是 认为 1 型糖尿病患者的 β 细胞被完全破坏。最近，这个教条被 长期 T1D 患者体内残留的胰岛素阳性 β 细胞的观察对这一问题提出了挑战。相似地， 在 T1D 的非肥胖糖尿病 (NOD) 小鼠模型中，有一个 β 细胞亚群能够 抵御长时间的免疫攻击。这些数据表明存在一群能够适应的β细胞 并在高压力条件下生存。为了以这些发现为基础，该提案的中心目标是 定义促进 β 细胞存活和预防 T1D 的途径。我假设快速激活 在 T1D 发病过程中，抗氧化反应会减少 β 细胞 ROS，从而抑制胰岛免疫原性。我会测试 这一假设有两个具体目标。目标 1 中的实验将研究 β 细胞如何选择性丧失 NRF2 有助于自身免疫性糖尿病的发生。在目标 2 中，我将确定控制机制 T1D 早期发病机制中 β 细胞 ROS 的减轻。这些目标的完成将决定职能作用和 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来预防 糖尿病条件下β细胞的破坏，以及作为这项工作的一部分开发和测试的工具可以 在未来的研究中用于将治疗或成像探针靶向 β 细胞。这些研究也将积极 影响我的职业生涯。全面了解早期糖尿病发病机制中的胰岛功能以及 使用尖端技术将使我能够发展成为一名科学家，并让我走上实现现实的轨道 以及对糖尿病研究领域的持久影响。该 F31 奖项需要为期 2 年的培训计划，旨在 实现 4 个主要目标：1) 加深对糖尿病研究技术和概念的理解，2) 培训用于糖尿病研究的靶向纳米颗粒的生成和使用以及药效学，3) 培训 口头和书面介绍研究成果，包括拨款准备，以及 4) 培训使用和 处理糖尿病研究的小鼠模型。此外，申请人还将受益于杰出和 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由以下人员组成的指导和咨询委员会 由 NIH 资助的经过精心挑选和组建的多元化团队组成。综上所述，建议 学习和培训目标将为申请人提供一个肥沃的培训环境，使她能够 成为一名多才多艺的独立研究人员，并加深对 β 细胞生理学的了解。