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：
10455673
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/10455673
关键词：
Address Animal Model Antigen Presentation Antigen Presentation Pathway Apoptotic Autocrine Communication Autoimmunity Back Beta Cell CXC chemokine receptor 3 CXCL10 gene CXCR3 gene Cell Communication Cell Line Cell Survival Cell physiology Cell surface Cells Chronic Clinic Complex Cytotoxic T-Lymphocytes DNA Data Diabetes Mellitus Disease Disease Outcome Endoplasmic Reticulum Environment Exposure to Failure Fibrinogen Functional disorder Funding Genes Genetic Genetic Transcription Glucose Goals Health Human Immune Tolerance Immunomodulators Impairment Inflammation Inflammation Mediators Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Knowledge Laboratories Lead Link Longevity Lymphocyte Major Histocompatibility Complex Mediating Mediator of activation protein Membrane Mentors MicroRNAs Natural Immunity Natural regeneration Nature Onset of illness Paracrine Communication Pathogenesis Pathologic Pathology Pathway interactions Patients Physiological Play 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 Tumor-infiltrating immune cells United States National Institutes of Health Vesicle Work activating transcription factor 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 immunogenic immunoregulation improved in vivo insulin secretion intercellular communication islet loss of function macrophage 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.

项目概要/摘要 1 型糖尿病 (T1D) 的特点是由于以下原因选择性破坏产生胰岛素的 β 细胞：浸润的自身攻击性 T 细胞和免疫耐受的破坏结果，患者会遇到这种情况。 β细胞功能和质量严重丧失，因此需要外源性胰岛素。改善疾病结果的免疫调节治疗策略收效甚微。因此，有必要采取新的策略来恢复 β 细胞的整体功能和健康。表明 β 细胞本身在 T1D 的进展过程中促进了自身的同谋死亡，因此可能作为潜在的干预治疗目标。已被证明会诱导 β 细胞功能障碍；然而，介导这一过程的机制尚未完全阐明。在本申请中，我们建议研究促炎介质对 β 细胞的影响。我们和其他人通过交换称为细胞外囊泡（EV）的循环纳米囊泡进行对话。注意到 T1D 亲和后 EV 货物在蛋白质和 miRNA 水平上发生显着含量变化然而，促炎细胞因子的直接生理和机制影响。将炎症性β细胞EV运送到受体β细胞的长期目标尚未完全阐明。申请人将建立一个独立的实验室，探索电动汽车的生理和机械作用该应用的中心假设是 β 细胞对其自身有贡献。通过致糖尿病 β 细胞 EV 货物交换诱导 β 细胞功能障碍和增强为了检验这一假设，提出了两个具体目标：在大量初步数据的支持下，我们将检验促炎性 β 细胞 EV 的假设。激活 CXCL10:CXCR3 轴以诱导 β 细胞衰竭在目标 2 中，我们将检验亲-细胞的假设。炎症性 β 细胞 EV 在 T1D 发病过程中有助于 β 细胞免疫调节。使用 T1D 和人类胰岛和细胞系的离体和体内小鼠模型来解决这些假设。申请人是高度协作的胰岛再生中心（再生医学中心）的一部分明尼苏达州罗彻斯特的梅奥诊所拥有出色的研究环境以及精心挑选的环境。 NIH 资助的研究人员将为申请人导师提供申请人指导委员会，该委员会由 NIH 资助的研究人员组成，将为申请人导师提供使自己成为一名独立研究调查员所需的工具和支持。