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

• 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
• 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

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.

项目总结/摘要 1型糖尿病（T1 D）的特征在于由于糖尿病引起的胰岛素产生β细胞的选择性破坏。 浸润性自身攻击性T细胞和免疫耐受性的破坏。因此，患者会遇到 β细胞功能和质量的严重丧失，因此需要外源性胰岛素。预防性 改善疾病结果免疫调节治疗策略的成功率很低。 因此，需要新的策略来恢复整体β细胞功能和健康。最近的证据 表明β细胞本身在T1 D的进展过程中促进了自身的协同死亡， 可以作为潜在的干预治疗靶点。慢性暴露于促炎介质 已被证明可诱导β细胞功能障碍;然而，介导这一过程的机制尚未完全阐明。 阐明。在本申请中，我们建议研究促炎介质对β细胞的影响， 通过称为细胞外囊泡（EV）的循环纳米囊泡的交换进行对话。我们和其他人 已经注意到，在T1 D pro-1后，EV货物在蛋白质和miRNA水平上的显著含量变化。 炎性细胞因子诱导。然而，改变的前体蛋白的直接生理和机制影响， 炎性β细胞EV货物到受体β细胞的作用尚未完全阐明。的长期目标 申请人将建立一个独立的实验室，探索EV在以下方面的生理和机制作用： T1 D的发病机制该申请的中心假设是β细胞有助于其自身的细胞增殖。 通过致糖尿病β细胞EV货物交换的死亡诱导β细胞功能障碍和增强 抗原加工和呈递。为了检验这一假设，提出了两个具体目标， 有大量的初步数据支持在目标1中，我们将检验促炎β细胞EV 激活CXCL 10：CXCR 3轴以诱导β细胞衰竭。在目标2中，我们将检验亲- 炎性β-细胞EV在T1 D的发病过程中有助于β-细胞免疫调节。两个目标将 使用T1 D的离体和体内小鼠模型以及人胰岛和细胞系来解决假设。的 申请人是高度合作的胰岛再生中心（再生医学中心）的一部分， 马约诊所，罗切斯特，明尼苏达州。这种优秀的研究环境除了精心挑选的 由NIH资助的研究人员组成的指导委员会将为申请人提供 必要的工具和支持，以建立自己作为一个独立的研究调查员。