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（由申请人提供）：1型糖尿病（T1 D）是由遗传易感个体中环境因素的复杂相互作用引发的胰岛素分泌胰腺细胞的自身免疫性破坏引起的。在该实验室进行的先前研究揭示了一组新的肽和相应的蛋白质，其使用基于液相色谱-质谱法（LC-MS）的蛋白质组学分析对来自具有有限样本量的糖尿病抗体标准化计划队列的人血清和血浆样本具有非常好的T1 D与健康对照的区分能力。该项目的长期目标是为临床社区提供全面验证的诊断和预后标志物，用于干预T1 D，并了解T1 D的发病机制，以最终预防T1 D。在本申请中，使用The Diabetes Autoimmunity in the Young Study（DAISY）作为母T1 D组群，我们将使用多重液相色谱-多反应监测-质谱（LC-MRM-MS）平台和最先进的完整蛋白质分离技术与高分辨率串联质谱联用，以大量测量这些生物标志物。（n = 2090）来自独立的大规模T1 D群组以及来自患有与T1 D具有相似临床和免疫学结果的疾病的个体的血清/血浆。具体而言，我们提出了以下目标：目标1，在独立的T1 D队列中建立标记肽的灵敏度，并提供这些肽在T1 D诊断中的准确阈值;目标2，使用2型糖尿病、乳糜泻和炎症性肠病的疾病对照建立标记肽的特异性;目的3，鉴定在该疾病发病机制中具有潜在作用的关键标志物肽的蛋白质异构体：目的4，在对研究者不知情的大规模临床T1 D队列中验证肽生物标志物;和目的5，用来自DAISY队列的纵向样本建立经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T1 D的实用性和特异性，进一步了解这种疾病的发病机制，并为T1 D预后，干预和预防的新策略提供基础。