Circulating Extracellular Vesicles in the Pathogenesis of Type 1 Diabetes

循环细胞外囊泡在 1 型糖尿病发病机制中的作用

• 批准号: 10475159
• 负责人: Susmita Sahoo
• 金额: $ 46.16万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475159
• 关键词: Address; Age; Alpha Cell; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Beta Cell; Biological Markers; Cell Death; Cell physiology; Cessation of life; Characteristics; Childhood; Code; Data; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Ethnic Origin; Event; Female; Functional disorder; Glucagon; Goals; Health; Human; Hyperglycemia; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Knowledge; Mediating; Mediator of activation protein; MicroRNAs; Mitochondria; Modeling; Molecular; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Patients; Plasma; Play; RNA; Research; Resistance; Rodent Model; Role; Severe Combined Immunodeficiency; Testing; Therapeutic; Untranslated RNA; clinical biomarkers; clinically relevant; cytotoxic; cytotoxicity; diabetes control; diabetic; differential expression; disease diagnosis; disorder control; early detection biomarkers; extracellular vesicles; functional loss; in vivo; insight; insulin dependent diabetes mellitus onset; insulin secretion; islet; non-diabetic; novel; novel therapeutics; sex; signature molecule; uptake

SUMMARY: Circulating Extracellular Vesicles in the Pathogenesis of Type 1 Diabetes Type 1 diabetes (T1D) is an autoimmune disease, characterized by death, dedifferentiation or dysfunction of functional beta cells. However, precise molecular events that initiate beta cell loss and dysfunction or mediate autoimmunity is a major gap in knowledge that remains unaddressed. Emerging evidence suggests that circulating extracellular vesicles (EVs), known mediators of intercellular microcommunication, may play important roles in the pathogenesis of T1D. However, their precise function and molecular contents, especially in the initiation of beta cell loss and dysfunction in humans are largely undefined. Here, we hypothesize that circulating EVs in T1D, through their distinct molecular characteristics, are cytotoxic to beta cell health, thus contributing to the pathogenesis of T1D, with the potential to serve as biomarkers for early disease diagnosis. Our preliminary data suggests that EVs, but not EV-depleted fraction in the humoral factors in T1D are cytotoxic, particularly to human beta cells, but not to alpha cells. Specifically, EVs from T1D subjects, but not from control subjects, induce human beta cell death suggesting that circulating T1D-EVs are key components contributing to humoral cytotoxicity. Therefore, characterizing T1D EVs at various stages of the disease and control could identify important biomarkers for early detection of the disease that correlate with beta cell loss and dysfunction. Our research plan has the following Specific Aims: AIM 1: To determine the functional effects of circulating EVs from pre-disease to late stage T1D subjects on human beta and alpha cell health. We will characterize circulating EVs from the plasma of T1D subjects at i) early (1-5 years), ii) late (>10 year) and iii) pediatric (<18 year) stages and compare them with i) autoantibody positive non-T1D, ii) T2D (control for secondary effects such as hyperglycemia) and iii) appropriate age, ethnicity, and sex-matched healthy control non-diabetic subjects for their effect on human beta and alpha cell health. AIM 2: To establish the functional role of circulating EVs in the pathogenesis of T1D in vivo using a rodent model. To provide proof-of-concept, we will administer circulating EVs from diabetic female NOD mice to non- diabetic controls and test T1D disease progression in the recipient (Aim2A); we will inhibit EV secretion in young pre-T1D female NOD mice and test T1D disease progression and quantify beta cell death and function (Aim2B). AIM 3: Investigate the molecular mechanisms, cargo composition and cargo function of human T1D- EVs. We will address the differential function of T1D EVs in beta cell cytotoxicity by investigating their uptake mechanisms, (Aim3A); compare EV cargo in T1D and control subjects (Aim3B); examine the function of differentially expressed EV-RNAs (Aim3C). Our proposed research is clinically relevant and will profoundly change our understanding of the progression of T1D. If successful, our study has the potential to identify new biomarkers and therapeutics for T1D.

摘要：1型糖尿病的发病机理中循环细胞外囊泡 1型糖尿病（T1D）是一种自身免疫性疾病，其特征是死亡，去分化或功能障碍 功能性β细胞。但是，启动β细胞丢失和功能障碍或介导的精确分子事件 自身免疫性是知识的主要差距，但仍未得到解决。新兴证据表明循环 细胞外囊泡（EV），已知的细胞间微通信介体，可能在 T1D的发病机理。但是，它们的精确功能和分子含量，尤其是在β的启动时 人类的细胞丧失和功能障碍在很大程度上是不确定的。 在这里，我们假设T1D中通过其独特的分子特征在T1D中循环EV是 细胞毒性对β细胞健康，因此有助于T1D的发病机理，有可能用作 早期疾病诊断的生物标志物。我们的初步数据表明EV，但不是电动汽车的分数 在T1D中的体液因子中是细胞毒性的，尤其是对人β细胞的细胞毒性，而不是α细胞。具体来说， 来自T1D受试者的电动汽车，但没有来自控制受试者的EV诱导人β细胞死亡，这表明循环 T1D-EV是导致体液细胞毒性的关键组成部分。因此，表征各种T1D EV 疾病和控制的阶段可以识别重要的生物标志物，以便早期发现该疾病 与β细胞损失和功能障碍相关。我们的研究计划具有以下具体目标： 目的1：确定从疾病前到后期T1D受试者的循环电动汽车的功能效应 关于人β和α细胞健康。我们将表征来自T1D受试者等离子体的循环电动 i）早期（1 - 5年），ii）（> 10年）和iii）小儿（<18年）阶段，并将其与i）自动抗体进行比较 阳性非T1D，ii）T2D（对高血糖等次要作用的对照）和iii）适当的年龄，种族， 以及性别匹配的健康对照非糖尿病受试者对人类β和α细胞健康的影响。 目标2：使用啮齿 模型。为了提供概念验证，我们将管理从糖尿病女性点头小鼠到非 - 受体中的糖尿病控制和测试T1D疾病进展（AIM2A）；我们将抑制年轻的EV分泌 T1D雌性点头小鼠和测试T1D疾病进展并量化β细胞死亡和功能（AIM2B）。 AIM 3：研究人T1D-的分子机制，货物组成和货物功能 电动汽车。我们将通过研究其摄取来解决beta细胞细胞毒性中T1D EV的差异功能 机制，（AIM3A）；比较T1D中的EV货物和控制对象（AIM3B）；检查的功能 差异表达的EV-RNA（AIM3C）。 我们拟议的研究在临床上具有相关性，并将深刻改变我们对 T1D。如果成功，我们的研究有可能识别T1D的新生物标志物和治疗剂。