Abnormal Extracellular Vesicles and Particles from Human Islets Impact T1D progression

来自人类胰岛的异常细胞外囊泡和颗粒影响 T1D 进展

基本信息

批准号：
10754074
负责人：
Shuibing Chen
金额：
$ 72.91万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-21 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754074
关键词：
Alpha Cell Antigen Presentation Antigen-Presenting Cells Apoptotic Beta Cell Binding Biological Markers Biology Blood Vessels Body Fluids Cell Communication Cell Line Cell Survival Cell membrane Cell physiology Cells Coxsackie Viruses DNA Databases Development Diagnosis Endocrine Endothelial Cells Field Flow Fractionation Functional disorder Heterogeneity Human Immune Insulin-Dependent Diabetes Mellitus Islet Cell Lipid Bilayers Lipids MLLT2 gene Macrophage Mediating Mediator Membrane Membrane Proteins Methods MicroRNAs Microfluidic Microchips Molecular Molecular Profiling Organ Organoids Outcome Pancreas Pathogenicity Pathologic Patient Care Patients Plasma Proteins Proteomics RNA Role Sampling Slice Stress Structure Technology Testing Tissues Ultracentrifugation Vascular blood supply Vascularization autoreactivity cell type cytokine diabetes pathogenesis exosome extracellular extracellular vesicles gain of function human pluripotent stem cell insulin dependent diabetes mellitus onset islet mouse model nanoparticle novel marker novel therapeutic intervention novel therapeutics particle prevent senescence signature molecule superresolution imaging

项目摘要

Abstract. Extracellular vesicles and particles (EVPs) are a group of heterogeneous nanoparticles that are secreted into the extracellular milieu by many types of cells. EVPs have emerged as important mediators in cell-to-cell communications within organs. Recent studies have suggested that EVPs might be involved in β cell-immune cell interaction and β cell dysfunction and survival in type 1 diabetes (T1D). However, many of these studies were performed using mouse models and not focused on human samples. Hence, there is a unmet need to understand the contribution of human islet/pancreas-associated EVPs in T1D progression. Here, we have assembled an interdisciplinary team, including experts in islet biology (Chen, Liu), EVP biology (Lyden), vascular biology (Rafii), and T1D patient care (Antal), to test the hypothesis that abnormal EVPs of pathogenic human islets and pancreatic tissues disrupt human islet function and survival and trigger T1D progression. We have performed extensive proteomics analyses of EVPs derived from human β cell lines cultured in T1D conditions. In addition, by comparing the plasma membrane protein profiles of human β cell line and primary human islet-derived EVPs with an EVP proteomic database containing 426 human samples, we have identified several plasma membrane protein candidates to isolate β cell-specific EVPs. Here, we will use multiple platforms, including primary human islets from healthy, pre-T1D, and T1D donors, human pluripotent stem cell (hPSC)-derived islet organoids, perfusable microfluidic devices containing vascularized islets, and pancreatic slice culture to systematically examine the role of human islet/pancreas-associated EVPs in islet cell function and survival during T1D progression. In this proposal, we expect to identify membrane-bound EVP protein panels to purify EVPs from human α, β cells, islets, and pancreatic tissue. We will define the EVP protein and RNA profiles and identify signature molecules associated with islet status during T1D progression. Moreover, we will systemically dissect the roles of human islet/pancreas EVPs in human β cell function and survival, as well as their role in the crosstalk between β cells and peri-islet cell niche. Overall, this study will facilitate the identification of novel “biomarkers” for T1D diagnosis and guide the development of new therapeutic strategies to treat and prevent the progression of T1D.

抽象的。细胞外囊泡和颗粒（EVP）是一组异质纳米颗粒，被分泌到许多类型的细胞的细胞外环境已成为细胞间的重要介质。最近的研究表明 EVP 可能参与 β 细胞免疫。然而，这些研究中有许多是关于 1 型糖尿病 (T1D) 中细胞相互作用、β 细胞功能障碍和生存的研究。是使用小鼠模型进行的，而不是针对人类样本，因此，存在未满足的需求。了解人类胰岛/胰腺相关 EVP 在 T1D 进展中的作用。在这里，我们组建了一个跨学科团队，包括胰岛生物学专家（陈、刘）、EVP生物学专家 (Lyden)、血管生物学 (Rafii) 和 T1D 患者护理 (Antal)，以检验异常 EVP 的假设致病性人类胰岛和胰腺组织破坏人类胰岛功能和存活并触发我们对源自人类 β 细胞系的 EVP 进行了广泛的蛋白质组学分析。此外，通过比较人 β 细胞系的质膜蛋白谱。和原代人类胰岛衍生的 EVP，其 EVP 蛋白质组数据库包含 426 个人类样本，我们已经确定了几种质膜候选蛋白来分离 β 细胞特异性 EVP。多个平台，包括来自健康、T1D 前和 T1D 供体的原代人类胰岛、人类多能干细胞 (hPSC) 衍生的胰岛类器官、含有血管化胰岛的可灌注微流体装置，以及胰腺切片培养系统地检查人胰岛/胰腺相关 EVP 在胰岛细胞中的作用 T1D 进展期间的功能和生存。在本提案中，我们期望鉴定膜结合 EVP 蛋白组，以从人类 α、β 中纯化 EVP 我们将定义 EVP 蛋白和 RNA 谱并识别特征。此外，我们将系统地剖析与 T1D 进展期间胰岛状态相关的分子。人胰岛/胰腺 EVP 在人 β 细胞功能和存活中的作用，以及它们在细胞间串扰中的作用总体而言，这项研究将有助于识别 T1D 的新型“生物标志物”。诊断并指导开发新的治疗策略来治疗和预防 T1D 的进展。