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

项目概要/摘要（30行或以下） 这项研究的前提来自于其他疾病的优先性，比如癌症， 心血管疾病、神经退行性疾病，以及与当前提议最相关的自身免疫性疾病，其中 细胞外囊泡（EV）在病理生理学中起作用，并且是用于早期检测的重要生物标志物。 然而，在人类1型糖尿病（T1 D）中，对细胞通信中的EV知之甚少。我们的整体 一种假说是，通过EV介导的胰岛和胰岛浸润性细胞之间的自分泌-旁分泌相互作用， 胰腺中的免疫细胞有助于T1 D的发展和进展。我们的具体目标是：1） 评估来自T1 D和自身抗体+（Aab+）的胰岛浸润性T细胞衍生EV（T-EV）的功能影响 供体对胰岛健康和不同免疫细胞群体的影响; 2）研究应激或 T1 D胰岛衍生EV（I-EV）对免疫细胞表型和胰岛健康的影响;以及3）破译差异蛋白 来自T1 D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， 研究人员拥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。 从36个T1 D或Aab阳性的人组织供体中，我们有>600个T细胞系直接从T1 D或Aab阳性的人组织中生长。 单个胰岛。我们拥有从胰岛中分离EV（I-EV）的专业知识和技术能力， 来自T1 D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 旁分泌和自分泌对胰岛健康和免疫细胞表型的影响。我们的研究计划是 从具有不同持续时间的T1 D或胰岛自身抗体阳性的供体产生T-EV和I-EV，以 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，其分子组成反映了播散细胞的病理生理状态。 这些研究将产生关于免疫细胞群体之间的通信的重要信息 以及T1 D的潜在生物标志物或治疗靶点。

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.