Mechanisms and Targeted Control of Pancreatic B-Cell Antioxidant Response

项目总结 1型糖尿病(T1D)是一种自身免疫性疾病，由产生胰岛素的β-1逐渐破坏引起。 细胞。免疫耐受性的丧失是易感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的发育和进展过程中， 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，它一直是 认为T1D患者的β-细胞被完全破坏。最近，这一教条被 挑战通过观察长期存在的T1D患者体内残留的胰岛素阳性β细胞。同样， 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 能抵御长期的免疫攻击。这些数据表明，有一群β细胞能够适应 并在高压力条件下存活。为了建立在这些发现的基础上，这项提案的中心目标是 明确促进β细胞存活和保护T1D的途径。我假设快速激活的是 在T1D发病过程中，抗氧化反应降低β细胞的ROS，从而抑制胰岛的免疫原性。我要测试一下 这一假说有两个具体目的。目标1的实验将研究β-细胞选择性丢失是如何 NRF2参与自身免疫性糖尿病的发生发展。在目标2中，我将确定控制机制 β细胞ROS在T1D早期发病机制中的缓解作用。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预防目标 β-在糖尿病形成条件下的细胞破坏，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靶向β细胞的治疗或成像探针。这些研究也将积极地 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，并使我走上实现 以及对糖尿病研究领域的持久影响。这项F31奖项需要一个为期两年的培训计划，旨在 实现4个主要目标：1)建立对糖尿病研究中的技术和概念的深入理解，2) 针对糖尿病研究的靶向纳米粒子和药效学的产生和使用方面的培训，3)培训 口头和书面介绍研究成果，包括准备赠款，以及4)培训使用和 糖尿病研究用小鼠模型的处理。此外，申请人将受益于尚未完成的和 印第安纳大学糖尿病和代谢疾病中心提供的协作研究环境 大学医学院。她的培训还将受益于一个指导和咨询委员会，该委员会由 由精心挑选和建立的NIH资助的调查人员组成的多样化团队。总括而言，建议的 学习和培训目标将为申请者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，并发展对β-细胞生理学的理解。

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.