Beta Cell Heterogeneity in the Interferon Alpha Response

干扰素α反应中的β细胞异质性

基本信息

批准号：
10751684
负责人：
Leslie Elaine Wagner
金额：
$ 4.77万
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：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2025-06-07
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751684
关键词：
ANXA5 gene Acute Address Advisory Committees Apoptosis Apoptotic Area Autoimmune Diseases Autoimmune Responses Award Beta Cell Biosensor Cells Communication Comprehension Coupled Cytoplasm Detection Development Diabetes Mellitus Disease Disease Progression Endoplasmic Reticulum Enterovirus Environment Event Fluorescence-Activated Cell Sorting Functional disorder Funding Future Gene Expression Genes Genetic Predisposition to Disease Genetic Risk Goals Grant Heterogeneity Human Hydrogen Peroxide Immune Immunofluorescence Immunologic In Vitro Indiana Individual Induction of Apoptosis Inflammatory Innate Immune System Insulin Insulin-Dependent Diabetes Mellitus Interferon alpha Interferons Interleukin-1 beta Islets of Langerhans Knowledge Label Laboratories Link MHC Class I Genes Metabolic Diseases Microscopy Mind Mitochondria Molecular Profiling Monitor Mus Nitric Oxide Oral Oranges Organelles Oxidative Stress Oxidative Stress Induction Pancreas Pathogenesis Patients Population Predisposition Prevalence Production Proteins Publishing Reactive Oxygen Species Research Research Personnel Residual state Risk Role Scientist Slice Stress Superoxides Techniques Testing Therapeutic Training United States National Institutes of Health Universities Virus Diseases Work Writing career development cytokine design diabetes pathogenesis diabetogenic differential expression dihydroethidium disorder prevention early childhood early onset endoplasmic reticulum stress experimental study improved in vivo insight insulin dependent diabetes mellitus onset intravital imaging islet medical schools mouse model non-diabetic novel novel therapeutics overexpression prevent ratiometric response single-cell RNA sequencing stressor therapeutic target transcriptomics

项目摘要

1 PROJECT SUMMARY 2 Type 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of insulin producing β-cells due 3 to a combination of genetic risk and an unknown environmental trigger. A leading hypothesis for the 4 environmental trigger is viral infection, during which the innate immune system releases various cytokines and 5 interferons. Interferon alpha (IFN-α) has been long implicated in disease pathogenesis, with its presence 6 observed in islets of donors with early-onset T1D. It has also been shown that IFN-α induces ER stress, MHC 7 class 1 overexpression, and islet apoptosis, classical hallmarks of T1D development. For many years it was 8 thought that all β-cells were destroyed in individuals with T1D. Recently, this dogma has been challenged with 9 the discovery of residual insulin positive β-cells in donors with long-standing T1D. This suggests that β-cells are 10 heterogeneous, with one population of β-cells able to survive conditions of high stress. With these observations 11 in mind, the central goal of this proposal is to understand mechanisms behind heterogeneity of human β-cell 12 ROS response following IFN-α insult. I hypothesize that ROS accumulating β-cells, termed ‘ROSponders’ 13 contain a unique molecular signature that promotes this heterogeneity in ROS accumulation, causing this subset 14 of cells to be more susceptible to oxidative stress and apoptosis. I will test this hypothesis through three specific 15 aims. Experiments in aim 1 are designed to characterize the molecular signature of ROSponders, with the goal 16 of identifying what makes them more susceptible to this ROS accumulation. In aim 2, I will determine the origin 17 of accumulating ROS. In aim 3, I will determine the fate of ROSponders through longitudinal intravital imaging. 18 With completion of these aims, the goal is to determine the mechanism and consequence of this observed 19 heterogeneity in ROS response. Importantly, through transcriptomics, this work will aim to identify novel targets 20 to prevent β-cell dysfunction under diabetogenic conditions, allowing for the development of future therapeutics 21 for disease prevention and/or treatment. A comprehensive understanding of islet function in early diabetes 22 pathogenesis and the use of cutting-edge techniques proposed in this grant will enable me to develop as a 23 scientist and set me on a trajectory to make real and lasting impacts in the field of diabetes. This F31 award 24 includes a 2-year training plan designed to achieve 4 main objectives: 1) develop a strong comprehension of 25 techniques and concepts used in diabetes research, 2) train in the use of different microscopy techniques, 3) 26 enhance written and oral scientific communication, and 4) train in the use and handling of mouse models for 27 diabetes research. In addition, I will benefit from the collaborative research environment provided by the Center 28 for Diabetes and Metabolic Diseases at the Indiana University School of Medicine. I will also benefit from an 29 advisory committee consisting of a diverse team of carefully selected and established NIH funded investigators 30 and a supportive research environment in the laboratory. 31 32 33 34

1 项目概要 2 1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是由于胰岛素产生的 β 细胞遭到破坏。 3 遗传风险和未知环境触发因素的结合。 4.环境触发因素是病毒感染，在此期间先天免疫系统释放各种细胞因子和 5 干扰素 α (IFN-α) 长期以来一直与疾病发病机制有关。 6 在早发性 T1D 捐献者的胰岛中观察到 IFN-α 会诱导 ER 应激、MHC。 7 1 类过度表达和胰岛细胞凋亡多年来一直是 T1D 发展的经典标志。 8 认为 1 型糖尿病患者的所有 β 细胞都被破坏。最近，这一教条受到了挑战。 9 在患有长期 T1D 的捐献者中发现残留的胰岛素阳性 β 细胞这表明 β 细胞是存在的。 10 种异质性的β细胞群体能够在高压力条件下生存。 11 请记住，该提案的中心目标是了解人类 β 细胞异质性背后的机制 12 IFN-α 损伤后的 ROS 反应我急忙发现 ROS 积累的 β 细胞，称为“ROSponders”。 13 含有独特的分子特征，可促进 ROS 积累的异质性，从而导致该子集 14 的细胞更容易受到氧化应激和细胞凋亡的影响，我将通过三个具体的方法来检验这一假设。目标 1 中的 15 个实验旨在表征 ROSponders 的分子特征，其目标是 16 确定是什么使它们更容易受到 ROS 积累的影响在目标 2 中，我将确定其来源。 17 积累 ROS 在目标 3 中，我将通过纵向活体成像确定 ROSponders 的命运。 18 完成这些目标后，目标是确定观察到的这一现象的机制和后果 19 ROS 反应的异质性重要的是，通过转录组学，这项工作旨在确定新的靶标。 20 预防糖尿病条件下的 β 细胞功能障碍，为未来治疗方法的开发奠定基础 21 用于疾病预防和/或治疗的全面了解早期糖尿病的胰岛功能。 22 这笔赠款中提出的发病机制和尖端技术的使用将使我能够发展成为一名 23 位科学家，这个 F31 奖项让我走上了在糖尿病领域产生真正和持久影响的道路。 24 包括旨在实现 4 个主要目标的 2 年培训计划： 1) 形成对糖尿病研究中使用的 25 种技术和概念，2) 培训不同显微镜技术的使用，3) 26 加强书面和口头科学交流，以及 4) 培训小鼠模型的使用和处理 27 此外，我还将受益于该中心提供的协作研究环境。 28 印第安纳大学医学院的糖尿病和代谢疾病我也将受益于印第安纳大学医学院的糖尿病和代谢疾病。 29 咨询委员会由精心挑选和成立的 NIH 资助的研究人员组成的多元化团队组成 30 以及实验室的支持性研究环境。 31 32 33 34