Biomarkers Of Beta Cell Stress In Type 1 Diabetes (BetaMarker)

描述（由申请人提供）：1型糖尿病（T1 D）的发病机制涉及细胞毒性T细胞和巨噬细胞在非常晚期介导的胰岛β细胞丢失。临床研究集中在诊断时给予免疫调节药物，然而，在这些研究中，没有一项研究实现了β细胞功能的恢复或持久保存。这些令人失望的结果质疑了我们对疾病发病机制的理解以及治疗时机（即疾病早期）是否可能产生更好的结果。该领域尚未满足的需求是开发简单可靠的生物标志物，其可以识别那些具有几乎确定或非常高的肿瘤标志物的人。 发展T1 D的可能性，从而允许早期治疗干预。我们的研究团队（Mirmira，Evans-Molina，Nadler，梅斯和Eizirik博士）和其他人最近的研究表明，在T1 D进化的早期，β细胞内触发的应激途径可能会启动和/或加速自身免疫介导的β细胞破坏。对β细胞的这种迟来的重视为改善当前的T1 D预测策略提供了独特的机会。本申请基于以下假设：糖尿病前期个体的应激β细胞将特定蛋白质和DNA物质释放到血浆中，并且多种此类物质的测量可以定义赋予发展T1 D的风险的β细胞“应激特征”。为了验证这一假设，我们组建了一个互动的科学家团队，他们将共同利用其蛋白质组学，功能基因组学，胰岛生物学和生物信息学/统计学专业知识来识别来自压力β细胞的蛋白质和核酸衍生的生物标志物，这些生物标志物可以更好地分层发展T1 D的风险。该项目名为“BetaMarker”，将采取双管齐下的方法：首先，将在DPT-1和TrialNet PTP队列的人类样本中测试候选β细胞特异性蛋白质和核酸生物标志物，第二，将采用全面的蛋白质组学和功能基因组学方法来发现新的β细胞特异性生物标志物，这些生物标志物将被重新用于人群测试。将实现三个目标：1。目的1：测试候选β细胞衍生蛋白生物标志物作为T1 D风险的预测因子。2.目的2：将差异甲基化的DNA种类作为T1 D中β细胞应激的生物标志物。3.目的3：鉴定β细胞应激和T1 D风险的新型蛋白质和核酸生物标志物。BetaMarker项目的影响将是开发一组反映β细胞“应激特征”的生物标志物，这些生物标志物将共同或作为T1 D发展风险评分的组成部分。

DESCRIPTION (provided by applicant): The pathogenesis of type 1 diabetes (T1D) involves islet beta cell loss mediated at a very late stage by cytotoxic T-cells and macrophages. Clinical studies have focused on the administration of immune modulatory drugs at the time of diagnosis, however, in none of these studies has the recovery or durable preservation of beta cell function been achieved. These disappointing outcomes have questioned both our understanding of the pathogenesis of the disease and whether timing of treatment (i.e. earlier in the disease) may yield better outcomes. An unmet need in the field has been the development of simple and reliable biomarkers that can identify those who have a virtually certain or very high likelihood of developing T1D, thereby allowing for earlier treatment interventions. Recent studies from our research Team (Drs. Mirmira, Evans-Molina, Nadler, Metz, and Eizirik) and others suggest the provocative concept that stress pathways triggered within the beta cell very early in T1D evolution may initiate and/or accelerate autoimmune-mediated beta cell destruction. This overdue emphasis on the beta cell offers a unique opportunity to improve current T1D prediction strategies. This application is based on the hypothesis that stressed beta cells of pre-diabetic individuals liberate specific protein and DNA species into plasma, and that measurement of multiple such species can define the beta cell "stress signature" that confers risk for developing T1D. To test this hypothesis, we have assembled an interactive Team of scientists that will collectively engage its proteomics, functional genomics, islet biology, and bioinformatics/statistics expertise to identify protein and nucleic acid-derived biomarkers emanating from stressed beta cells that can stratify better the risk of developing T1D. This project, called "BetaMarker," will take a two-pronged approach: in the first, candidate beta cell-specific protein and nucleic acid biomarkers will be tested in human samples from the DPT-1 and TrialNet PTP cohorts, and in the second, a comprehensive proteomics and functional genomics approach will be undertaken to discover new beta cell-specific biomarkers that will be funneled back into testing in human populations. Three aims will be achieved: 1. Aim 1: Test candidate beta cell-derived protein biomarkers as predictors of T1D risk. 2. Aim 2: Validate differentially methylated DNA species as biomarkers of beta cell stress in T1D. 3. Aim 3: Identify novel protein and nucleic acid biomarkers of beta cell stress and T1D risk. The impact of the BetaMarker project will be the development of a group of biomarkers that reflect the beta cell "stress signature" and that will serve collectively or as components in a risk score for the development of T1D.