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个项目摘要 2型1型糖尿病（T1D）是一种自身免疫性疾病，其特征是胰岛素产生β细胞应得 3结合了遗传风险和未知的环境触发因素。一个主要假设 4环境触发是病毒感染，在此期间，先天免疫系统释放了各种细胞因子和 5个干扰素。干扰素α（IFN-α）长期与疾病发病机理有关 6在具有早发T1D的供体的胰岛中观察到。还显示IFN-α诱导ER应力，MHC 7类过表达和胰岛凋亡，T1D发育的经典标志。多年来一直是 8认为所有β细胞在T1D的个体中都被破坏了。最近，这种教条受到了挑战 9在具有长期T1D的供体中发现残留的胰岛素阳性β细胞。这表明β细胞是 10异质，其中一个β细胞能够生存高应激条件。与这些观察结果 11牢记，该提案的核心目标是了解人β细胞异质性背后的机制 IFN-α侮辱后的12个ROS响应。我假设ROS积累了β细胞，称为“ Rosponders” 13包含一个独特的分子特征，可促进ROS积累中的这种异质性，从而导致该子集 14个细胞更容易受到氧化物胁迫和凋亡的影响。我将通过三个特定的特定来检验这一假设 15个目标。 AIM 1中的实验旨在表征Rosponders的分子特征，目标 16确定是什么使它们更容易受到ROS积累的影响。在AIM 2中，我将确定起源累积ROS的17。在AIM 3中，我将通过纵向插入式成像来确定竞技场的命运。 18随着这些目标的完成，目标是确定所观察到的机制和结果 ROS响应中的19个异质性。重要的是，通过转录组学，这项工作将旨在确定新的目标 20可预防糖尿病生成状况下的β细胞功能障碍，从而发展未来的治疗 21用于预防疾病和/或治疗。对早期糖尿病的胰岛功能的全面了解 22本赠款中提出的发病机理和使用尖端技术将使我能够发展为 23科学家，让我踏上了一条轨迹，以对糖尿病领域产生真实和持久的影响。这个F31奖 24包括一项为期2年的培训计划，旨在实现4个主要目标：1）对 25种糖尿病研究中使用的技术和概念，2）使用不同显微镜技术的训练，3） 26增强书面和口头科学交流，以及4）在使用和处理鼠标模型的训练 27糖尿病研究。此外，我将从中心提供的协作研究环境中受益 28印第安纳大学医学院的糖尿病和代谢疾病。我还将从一个 29咨询委员会由一组精心挑选和成立的NIH资助的调查人员组成 30和实验室支持的研究环境。 31 32 33 34