Extracellular Vesicle-mediated islet immune cross talk in Type 1 Diabetes pathogenesis

1 型糖尿病发病机制中细胞外囊泡介导的胰岛免疫串扰

基本信息

批准号：
10703429
负责人：
SALLY Choate KENT
金额：
$ 75.11万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703429
关键词：
Address Affect Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autologous Beta Cell CD8B1 gene Cardiovascular Pathology Cardiovascular system Cell Communication Cell Line Cell Separation Cell physiology Cells Characteristics Communication Data Dendritic Cells Development Diabetes Mellitus Disease Environment Family Functional disorder Goals Hand Health Human Immune Individual Inflammation Inflammatory Innate Immune System Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Malignant Neoplasms Mediating Mediator Membrane Molecular National Institute of Diabetes and Digestive and Kidney Diseases Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Organ Organ Donor Pancreas Pathogenesis Patients Peripheral Phenotype Population Proteins Research Research Personnel Resources Role STEM research Signal Transduction Slice Source Spleen Stress T cell infiltration T cell response T-Cell Activation T-Lymphocyte Techniques Testing Tissue Donors Tissue Sample Tissues Vesicle autocrine cell type cytokine cytotoxic cytotoxicity diabetes pathogenesis early detection biomarkers extracellular vesicles human tissue immune cell infiltrate inflammatory milieu insight intercellular communication islet islet cell antibody monocyte neurological pathology novel paracrine potential biomarker therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT (30 lines or less) The premise for the proposed research stems from precedence in other diseases, such as cancer, cardiovascular, neurodegenerative, and most relevant to the current proposal, autoimmune diseases, in which extracellular vesicles (EVs) play a role in the pathophysiology and are important biomarkers for early detection. However, in human type 1 diabetes (T1D), little is known concerning EVs in cellular communication. Our overall hypothesis is that autocrine-paracrine interactions, mediated through EVs, between the islets and islet-infiltrating immune cells in the pancreas contribute to the development and progression of T1D. Our specific aims are: 1) to assess the functional impact of islet-infiltrating T-cell derived EVs (T-EV) from T1D and autoantibody+ (Aab+) donors on islet health and on distinct immune cell populations; 2) to investigate the contribution of stressed or T1D islet-derived EVs (I-EV) on immune cell phenotype and islet health; and 3) to decipher the differential protein cargo in T-EV and I-EV from T1D and Aab+ donors. To address these aims, we have assembled a team of investigators with highly relevant expertise, techniques and unique resources of cell lines and tissue samples. From 36 human tissue donors with T1D or Aab positivity, we have >600 T cell lines grown directly from the individual islets of pancreata. We have the expertise and technical ability to isolate EV from islets (I-EV) and from islet-infiltrating T cell lines (T-EV) from T1D donors. Our preliminary data indicates I-EV and T-EV have both paracrine and autocrine effects on islet health and immune cell phenotype. Our Research Plan is to generate T-EV and I-EV from donors with T1D of distinct durations or positivity for islet autoantibodies, to evaluate their effects on islet health and immune cell function, and to determine the uniquely packaged protein cargo from these EVs whose molecular composition reflects the pathophysiologic state of the disseminating cell. These studies will yield important information concerning the communication between immune cell populations and islets via EVs in the pathogenesis of T1D, and potential biomarkers or therapeutic targets for T1D.

项目摘要/摘要（30 行或更少）拟议研究的前提源于其他疾病的先例，例如癌症、心血管疾病、神经退行性疾病以及与当前提案最相关的自身免疫性疾病，其中细胞外囊泡（EV）在病理生理学中发挥作用，是早期检测的重要生物标志物。然而，在人类 1 型糖尿病 (T1D) 中，人们对 EV 在细胞通讯中的作用知之甚少。我们的整体假设是通过 EV 介导的胰岛和胰岛浸润之间的自分泌-旁分泌相互作用胰腺中的免疫细胞有助于 T1D 的发生和进展。我们的具体目标是：1）评估来自 T1D 的胰岛浸润 T 细胞衍生的 EV (T-EV) 和自身抗体+ (Aab+) 的功能影响捐献者对胰岛健康和不同免疫细胞群的贡献； 2）调查压力或压力的贡献 T1D 胰岛源性 EV（I-EV）对免疫细胞表型和胰岛健康的影响； 3) 破译差异蛋白来自 T1D 和 Aab+ 供体的 T-EV 和 I-EV 中的货物。为了实现这些目标，我们组建了一个团队具有高度相关的专业知识、技术和独特的细胞系和组织样本资源的研究人员。我们拥有超过 600 个 T 细胞系，来自 36 名 T1D 或 Aab 阳性的人体组织捐献者，直接从单个胰岛。我们拥有从胰岛中分离 EV 的专业知识和技术能力 (I-EV) 来自 T1D 供体的胰岛浸润 T 细胞系 (T-EV)。我们的初步数据表明 I-EV 和 T-EV 已旁分泌和自分泌都会对胰岛健康和免疫细胞表型产生影响。我们的研究计划是从具有不同持续时间或胰岛自身抗体阳性的 T1D 捐献者中生成 T-EV 和 I-EV，评估它们对胰岛健康和免疫细胞功能的影响，并确定独特包装的蛋白质来自这些 EV 的货物其分子组成反映了传播细胞的病理生理状态。这些研究将产生有关免疫细胞群之间交流的重要信息和胰岛通过 EVs 在 T1D 发病机制中的作用，以及 T1D 的潜在生物标志物或治疗靶点。