Functional and molecular characterization of the human islet interferon alpha response

人胰岛干扰素α反应的功能和分子特征

• 批准号: 10264921
• 负责人: Amelia K Linnemann
• 金额: $ 15.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2023-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264921
• 关键词: Acute; Address; Affect; Apoptosis; Appearance; Autoantibodies; Autoimmune Diabetes; B-Lymphocytes; Beta Cell; Biosensor; Blood Cells; Cell Death; Cell Survival; Cells; Child; Cytometry; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disease; Event; Exhibits; Exposure to; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Heterogeneity; Human; Image; Immune; Immune system; Impairment; Inbred NOD Mice; Incidence; Individual; Innate Immune Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferon-alpha; Interferons; Intervention; Invaded; Investigation; Islet Cell; Islets of Langerhans; Lasers; Lead; Link; Living Donors; Measures; Mediating; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Organ Donor; Outcome; Pancreas; Pathogenesis; Pathway interactions; Phenotype; Population; Population Heterogeneity; Populations at Risk; Prediabetes syndrome; Proteins; Reactive Oxygen Species; Recovery of Function; Resistance; Risk; Role; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; Time; Transplantation; United States; Virus; Work; Xenograft Model; animal imaging; autoimmune pathogenesis; cost estimate; design; diabetes pathogenesis; endoplasmic reticulum stress; experimental study; extracellular; functional outcomes; glycemic control; illness length; imaging study; in vivo; in vivo imaging; inhibitor/antagonist; insulin dependent diabetes mellitus onset; insulitis; interest; intravital imaging; islet; mouse model; new therapeutic target; novel; overexpression; patient population; prevent; response; survival outcome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Type 1 diabetes is a result of β-cell death, or apoptosis of the insulin-producing cells in the pancreas. However, we are currently limited in our understanding of the molecular events that are involved in the initiation of pancreatic β-cell apoptosis and on the role for β-cell heterogeneity in the pathogenesis of type 1 diabetes. Interferon (IFN)-α-mediated signaling is a key component of type 1 diabetes pathophysiology. Children genetically at risk for type 1 diabetes have a type I IFN-inducible transcriptional signature in blood cells that precedes appearance of autoantibodies. Type I IFN is also expressed in pancreatic islets from people with type 1 diabetes and laser-captured islets from living donors with recent onset type 1 diabetes show an increase in IFN-stimulated genes. IFN-α induces ER stress, insulitis, and a massive HLA class I overexpression in human β-cells, three hallmarks of type 1 diabetes. Collectively, these observations suggest a critical role for IFN-α signaling in the crosstalk between β-cells and the immune system in early type 1 diabetes. Using a xenograft model and live animal imaging studies, we recently made the novel observation that IFN-α stimulates a rapid accumulation of reactive oxygen species (ROS) within a subset of human β-cells. It is well established that β- cells are exquisitely sensitive to ROS accumulation, and a maladaptive response to ROS can lead to β-cell apoptosis. Therefore, we hypothesize that human β-cells exhibiting rapid ROS accumulation in response to IFN- α within the islet have a unique molecular signature that predisposes them to early apoptosis in T1D pathogenesis. To test this hypothesis, we will characterize the subset of cells exhibiting rapid accumulation of ROS in response to IFN-α exposure in vivo and determine whether these cells are selectively targeted for early apoptosis. The experiments outlined in the current proposal are specifically designed to identify and characterize some of the key early events associated with β-cell apoptosis in human islets, with the long-term goal of identifying novel therapeutic targets to prevent diabetes in the at-risk population.

项目摘要/摘要 在过去的几次 几十年。 1型糖尿病是β细胞死亡的结果，或胰腺中产生胰岛素细胞的凋亡。 但是，我们目前对倡议中涉及的分子事件的理解有限 胰腺β细胞凋亡以及β细胞异质性在1型糖尿病发病机理中的作用。 干扰素（IFN）-α介导的信号传导是1型糖尿病生理学的关键组成部分。孩子们 从遗传上有1型糖尿病的风险，在血细胞中具有I型I型IFN诱导的转录特征 在自身抗体的外观之前。 I型IFN也以类型的人的胰岛胰岛表达 1型发病型糖尿病的1个糖尿病和激光捕获胰岛显示出增加 IFN刺激的基因。 IFN-α诱导人类的ER应力，胰岛炎和大量HLA I类过表达 β细胞，1型糖尿病的三个标志。总的来说，这些观察结果表明IFN-α至关重要 早期1型糖尿病中β细胞与免疫系统之间的串扰中的信号传导。使用异种移植 模型和现场动物成像研究，我们最近进行了新的观察结果，即IFN-α刺激了快速 人β细胞子集中活性氧（ROS）的积累。很好地确定β- 细胞对ROS的积累完全敏感，并且对ROS的适应不良反应会导致β细胞 凋亡。因此，我们假设人β细胞响应于IFN- 胰岛内的α具有独特的分子特征，使它们易于T1D早期凋亡 发病。为了检验这一假设，我们将表征显示出表现出的细胞的子集 ROS响应体内IFN-α暴露，并确定这些细胞是否被选择性地针对早期 凋亡。当前建议中概述的实验是专门设计的，以识别和表征 人类小岛中与β细胞凋亡相关的一些关键早期事件，其长期目标的 识别新型的热靶标，以预防高危人群中的糖尿病。