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： 浸润自身攻击性 T 细胞并破坏免疫耐受。结果，患者遇到了 β细胞功能和质量严重丧失，因此需要外源性胰岛素。预防性 改善疾病结果的免疫调节治疗策略收效甚微。 因此，需要采取新的策略来恢复 β 细胞的整体功能和健康。最近的证据 表明 β 细胞本身在 T1D 的进展过程中促进了自身的共谋死亡，因此 可以作为潜在的干预治疗靶点。长期接触促炎介质 已被证明可诱导 β 细胞功能障碍；然而，调解这一过程的机制尚未充分建立 阐明了。在此应用中，我们建议研究促炎介质对 β 细胞的影响 通过交换被称为细胞外囊泡（EV）的循环纳米囊泡进行对话。我们和其他人 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 炎症细胞因子诱导。然而，亲和力改变的直接生理学和机械学意义 炎症性 β 细胞 EV 转运至受体 β 细胞的机制尚未完全阐明。该组织的长期目标 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 T1D 的发病机制。该应用的中心假设是 β 细胞有助于其自身 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 抗原加工和呈递。为了检验这一假设，提出了两个具体目标： 有大量初步数据支持。在目标 1 中，我们将检验促炎性 β 细胞 EV 的假设 激活 CXCL10:CXCR3 轴诱导 β 细胞衰竭。在目标 2 中，我们将检验以下假设： 在 T1D 发病过程中，炎症性 β 细胞 EV 有助于 β 细胞免疫调节。这两个目标都将 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。这 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 梅奥诊所，明尼苏达州罗切斯特。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 使自己成为一名独立研究调查员所需的工具和支持。