Role of Small Extracellular Vesicles in Beta Cell Failure and Autoimmunity in Type 1 Diabetes Mellitus

小细胞外囊泡在 1 型糖尿病 β 细胞衰竭和自身免疫中的作用

基本信息

批准号：
10673047
负责人：
Naureen Javeed
金额：
$ 15.31万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673047
关键词：
Address Animal Model Antigen Presentation Antigen Presentation Pathway Apoptosis Apoptotic Autocrine Communication Autoimmunity Beta Cell Binding CXC chemokine receptor 3 CXCL10 gene CXCR3 gene Cell Communication Cell Line Cell Proliferation Cell Survival Cell physiology Cell surface Cells Chronic Clinic Complex Cytotoxic T-Lymphocytes DNA Data Diabetes Mellitus Disease Outcome Disease Progression Endoplasmic Reticulum Environment Exposure to Failure Functional disorder Funding Genes Genetic Genetic Transcription Glucose Goals Health Homeostasis Human Hyperglycemia Immune Tolerance Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intervention Knowledge Laboratories Link Lipids Longevity Lymphocyte Macrophage Major Histocompatibility Complex Mediating Mediator Membrane Mentors MicroRNAs Natural Immunity Natural regeneration Nature Onset of illness Paracrine Communication Pathogenesis Pathologic Pathology Pathway interactions Patients Physiological Play Population Predisposition Preventive treatment Process Proteins RNA Receptor Inhibition Regenerative Medicine Reporting Research Research Personnel Role STAT1 gene Signal Transduction Stress Structure of beta Cell of islet Susceptibility Gene T-Lymphocyte Testing Therapeutic Intervention Transcript United States National Institutes of Health Vesicle Work adaptive immunity autoimmune pathogenesis blood glucose regulation cell type chemokine cytokine cytotoxic CD8 T cells diabetes pathogenesis diabetogenic effector T cell endoplasmic reticulum stress exosome extracellular vesicles gene network immune cell infiltrate immune modulating agents immunogenic immunoregulation improved in vivo insulin secretion intercellular communication islet loss of function microvesicles migration mouse model nanovesicle new therapeutic target novel novel marker novel strategies novel therapeutic intervention preservation recruit response stressor success therapeutic target tool transcription factor treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is characterized by the selective destruction of insulin producing β-cells due to infiltrating autoaggressive T-cells and a break in immune tolerance. As a consequence, the patient is met with a severe loss of β-cell function and mass thus requiring the need for exogenous insulin. Preventative immunomodulatory therapeutic strategies to improve disease outcome have been met with minimal success. Therefore, novel strategies to restore overall β-cell function and health are warranted. Recent evidence suggests that β-cells themselves facilitate their own complicit demise during the progression of T1D and thus may serve as potential therapeutic targets of intervention. Chronic exposure to pro-inflammatory mediators has been shown to induce β-cell dysfunction; however, the mechanisms mediating this process have yet to be fully elucidated. In this application, we propose to study the impact of pro-inflammatory mediators on the β-cell dialogue through exchange of circulating nanovesicles termed extracellular vesicles (EVs). We and others have noted significant content alterations in EV cargoes at the protein and miRNA level upon T1D pro- inflammatory cytokine induction. However, the direct physiological and mechanistic implications of altered pro- inflammatory β-cell EV cargo to recipient β-cells have yet to be fully elucidated. The long-term goal of the applicant is to establish an independent laboratory exploring the physiological and mechanistic role of EVs in the pathogenesis of T1D. The central hypothesis of the application is that β-cells contribute to their own demise through diabetogenic β-cell EV cargo exchange to induce β-cell dysfunction and enhancement of antigen processing and presentation. To test this hypothesis, two specific aims have been proposed which are backed by extensive preliminary data. In Aim 1, we will test the hypothesis that pro-inflammatory β-cell EVs activate the CXCL10:CXCR3 axis to induce β-cell failure. In Aim 2, we will test the hypothesis that pro- inflammatory β-cell EVs contribute to β-cell immunomodulation during the pathogenesis of T1D. Both Aims will use ex vivo and in vivo mouse models of T1D and human islets and cell lines to address the hypotheses. The applicant is part of the highly collaborative Islet Regeneration Center (Center for Regenerative Medicine) at Mayo Clinic, Rochester, MN. This outstanding research environment in addition to a carefully selected mentoring committee comprised of established NIH-funded investigators will provide the applicant with the necessary tools and support to establish herself as an independent research investigator.

项目摘要/摘要 1型糖尿病（T1D）的特征是由于选择性破坏胰岛素而产生的β细胞。浸润自身攻击T细胞和免疫耐受性破裂。结果，患者遇到了 β细胞功能的严重丧失和质量，因此需要外源性胰岛素。预防性改善疾病结局的免疫调节治疗策略已获得最低的成功。因此，有必要恢复整体β细胞功能和健康的新策略。最近的证据表明β细胞本身促进了他们在T1D进展过程中的同谋灭亡，因此可以作为干预措施的潜在治疗靶标。长期暴露于促炎性介体的暴露被证明会诱导β细胞功能障碍；但是，介导该过程的机制尚未完全阐明。在此应用中，我们建议研究促炎性介体对β细胞的影响通过交换所谓的细胞外蔬菜（EV）的循环纳米层的对话。我们和其他人已经注意到蛋白质和miRNA水平的EV货物的含量改变在T1D pro- 炎性细胞因子诱导。但是，改变的直接生理和机理含义炎症性β细胞EV货物到受体β细胞尚未完全阐明。长期目标申请人将建立一个独立的实验室，探讨电动汽车在 T1D的发病机理。应用的中心假设是β细胞有助于自己通过糖尿病性β细胞EV货物交换来诱导β细胞功能障碍和增强抗原加工和表现。为了检验这一假设，已经提出了两个具体目标由广泛的初步数据支持。在AIM 1中，我们将测试促炎性β细胞EV的假设激活CXCL10：CXCR3轴以诱导β细胞衰竭。在AIM 2中，我们将检验以下假设炎症β细胞电动汽车在T1D发病机理期间有助于β细胞免疫调节。两个目标都会使用T1D和人类胰岛和细胞系的体内和体内小鼠模型来解决这些假设。这申请人是高度协作胰岛再生中心（再生医学中心）的一部分明尼苏达州罗切斯特的梅奥诊所。除了精心挑选的那样，这种杰出的研究环境已建立的NIH资助的调查人员完成的指导委员会将为申请人提供必要的工具和支持，以确立自己为独立研究人员。