权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘