Validation of Novel Peptide/Protein Markers for Diagnosis of Type 1 Diabetes

用于诊断 1 型糖尿病的新型肽/蛋白质标记物的验证

• 批准号: 8495451
• 负责人: Thomas O Metz
• 金额: $ 92.38万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495451
• 关键词: Affect; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biochemical; Biological Assay; Biological Markers; Blinded; Celiac Disease; Cells; Clinical; Cohort Studies; Communities; Complex; Coupled; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Progression; Environmental Risk Factor; Foundations; Functional disorder; Goals; Human; Immune; Immune response; Incidence; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Liquid Chromatography; Mass Spectrum Analysis; Measurement; Measures; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pancreas; Parents; Pathogenesis; Patients; Peptides; Plasma; Prevention; Preventive Intervention; Prognostic Marker; Protein Isoforms; Proteins; Proteolytic Processing; Proteomics; Reproducibility; Research; Research Personnel; Resolution; Role; Sample Size; Sampling; Serum; Specificity; Standardization; Technology; Validation; base; blind; clinical Diagnosis; cohort; community intervention; disorder control; in vivo; insight; islet; liquid chromatography mass spectrometry; multiple reaction monitoring; novel; outcome forecast; prognostic; programs; protein structure; tandem mass spectrometry; type I and type II diabetes

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic ¿-cells triggered by complex interactions of environmental factors in genetically predisposed individuals. Previous studies carried out in this laboratory revealed a panel of novel peptides and corresponding proteins having very good discriminating power of T1D from healthy controls using liquid chromatography-mass spectrometry (LC-MS) based proteomics analyses of human blood serum and plasma samples from a Diabetes Antibody Standardization Program cohort with limited sample size. The long-term goal of this project is to provide thoroughly validated diagnostic and prognostic markers to the clinical community for intervention of T1D, and to understand the pathogenesis of T1D for its ultimate prevention. In the present application, using The Diabetes Autoimmunity in the Young Study (DAISY) as a parent T1D cohort, we will use our multiplexed liquid chromatography- multiple reaction monitoring-mass spectrometry (LC-MRM-MS) platform and state-of-the-art technologies on intact protein separation coupled with high resolution tandem mass spectrometry to measure these biomarkers in large numbers (n = 2090) of blood serum/plasma from independent, large scale T1D cohorts, as well as from individuals having diseases that share similar clinical and immunological outcomes with T1D. Specifically, we propose the following aims: Aim 1, to establish the sensitivity of marker peptides in an independent T1D cohort and provide accurate threshold values of these peptides in diagnosis of T1D; Aim 2, to establish the specificity of marker peptides using disease controls of type 2 diabetes, celiac disease and inflammatory bowel disease; Aim 3, to identify the protein isoforms of key marker peptides having potential roles in pathogenesis of this disease; Aim 4, to validate the peptide biomarkers in large scale clinical T1D cohorts blinded to the investigators; and Aim 5, to establish the prognostic value of validated peptide biomarkers with longitudinal samples from the DAISY cohort. The outcome of the proposed research will confirm the utility and specificity of these peptide/protein markers for diagnosing T1D, gain further insight to the pathogenesis of this disease, and provide foundations for new strategies in T1D prognosis, intervention and prevention.

描述（由应用程序提供）：1型糖尿病（T1D）由胰岛素产生胰岛的自身免疫性破坏引起，这些细胞是由环境因素在一般偏见的个体中的复杂相互作用触发的。在该实验室中进行的先前研究表明，使用液态色谱 - 质谱法（LC-MS）的蛋白质组学分析，具有非常好的T1D的新型肽和相应的蛋白质，具有非常好的T1D的能力，可以从糖尿病和糖尿病抗体标准化程序群体中，具有限量样品大小。该项目的长期目标是向临床界提供彻底验证的诊断和预后标记，以进行T1D的干预，并了解T1D的发病机理以防止其最终。在介绍应用中，使用糖尿病在年轻研究（DAISY）中作为家长T1D队列中的自身免疫性，我们将使用我们的多重液相色谱法 - 多重反应监测质量光谱法（LC-MRMM-MS）平台和最先进的蛋白质技术与完整的蛋白质分离，与高分辨率群体互联9次互联体量子群，以衡量这些9的量度9，从来自独立，大规模T1D队列的血清/血浆以及与T1D具有相似临床和免疫学结果的疾病的人的血清/血浆。具体而言，我们提出以下目的：目标1，以在独立的T1D队列中建立标记肽的敏感性，并在T1D诊断中提供这些肽的准确阈值；目的2，使用2型糖尿病，腹腔疾病和炎症性肠病的疾病控制建立标记肽的特异性；目的3，确定关键标记肽的蛋白质同工型在该疾病的发病机理中可能作用；目标4，以大规模的临床T1D队列验证肽生物标志物对研究人员视而不见；目标5，以建立具有雏菊队列的纵向样品的经过验证的肽生物标志物的预后价值。拟议研究的结果将证实这些肽/蛋白质标记物用于诊断T1D的效用和特异性，进一步了解该疾病的发病机理，并为T1D预后，干预和预防的新策略提供基础。