T1D:Investigating the Gut Microbiome, Urinary Proteome and Metabolome

T1D：研究肠道微生物组、尿液蛋白质组和代谢组

• 批准号: 8241486
• 负责人: REMBERT PIEPER
• 金额: $ 470.09万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241486
• 关键词: Adolescent; Affect; Antibodies; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biological; Biological Assay; Biological Markers; Biometry; Blood; Blood Glucose; C-Type Lectins; Cells; Cessation of life; Child; Chronic; Classification; Clinic; Clinical; Clinical Data; Cohort Studies; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Data Set; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Distal; Early Diagnosis; Enterovirus; Environmental Risk Factor; Epidemiologic Studies; Equipment and supply inventories; Etiology; Family; Feces; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; Gold; Immune system; Incidence; Individual; Infection; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor; Intervention; Intestines; Islets of Langerhans; Lead; Left; Link; Machine Learning; Metabolic; Metabolism; Metadata; Metagenomics; Methods; Microbe; Molecular; Molecular Profiling; Mucosal Immune Responses; Onset of illness; Pancreas; Pathogenesis; Patients; Pattern; Phase; Phylogeny; Pilot Projects; Play; Populations at Risk; Predictive Value; Protein Tyrosine Phosphatase; Proteome; Proteomics; Publishing; Recording of previous events; Resolution; Ribosomal RNA; Risk; Risk Assessment; Role; Sampling; Siblings; Staging; Surveys; Susceptibility Gene; Taxonomy; Techniques; Technology Transfer; Testing; Therapeutic Intervention; Time; Urinary tract; Urine; Viral; base; biosignature; cell injury; clinical Diagnosis; cohort; disorder risk; gut microbiota; insight; insulin dependent diabetes mellitus onset; islet; loss of function; metabolomics; metagenomic sequencing; microbial; microbiome; multiple reaction monitoring; novel; patient population; prospective; protein metabolite; trait; urinary

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disorder characterized by the loss of function of insulin producing pancreatic cells leading to myriad manifestations of the disease in affected individuals. When left untreated this can lead to death. Many studies have shown that development of the disease is the result of interactions between immunological, genetic, and environmental factors. Although, many environmental factors have been implicated, the mechanisms of involvement or major determinants are yet to be clearly identified. Published studies have suggested that T1D results from environmental triggers acting on genetically susceptible individuals and that microbial infection and their immunological consequences are suspected to take part in the pathogenesis. Several mechanisms have been proposed for the causation of beta-cell damage by microbes. Data from retrospective and prospective epidemiological studies strongly suggest the involvement of enteroviruses in the development of T1D. Altered microbial diversity in the gut microbiota has been shown to trigger an abnormal mucosal immune response to further the progression of T1D. Genetic susceptibility traits for T1D are becoming more numerous, including loci for HLA, insulin, protein tyrosine phosphatase-22, cytotoxic T-lymphocyte-associated protein 4, the interleukin-2 receptor and C- type lectin. This complexity renders them less desirable as predictive tests. Although genetic susceptibility genes are known to play a substantial role in the development of T1D, cellular changes as well as environmental triggers may serve as excellent, potentially more universal biomarkers for risk assessment. For this study, we propose to analyze blood, stool and urine samples from children and adolescent patient populations who have been recently diagnosed with T1D, their siblings, and at-risk cohorts from the TrialNet network (www.diabetestrialnet.org). We propose to apply high-throughput genomics, proteomics and metabolomics techniques to identify molecular signatures discriminating these cohorts. By deconvolution of high-resolution molecular data, we expect to identify viral-microbial specific correlated patterns of proteins and metabolites. Our aim is to discover and verify candidate biomarkers from a large number of biological constituents; from genomic, proteomic and metabolomic datasets through correlation of host microbiome data and genotype. Our purpose is to advance non-invasive clinical tests by applying novel molecular methods to correlate disease status for early diagnosis and prediction of T1D onset, setting the stage for potential therapies or intervention strategies. PUBLIC HEALTH RELEVANCE: The incidence of Type I Diabetes (T1D) has been rising rapidly in children and adolescents over the last 20 years. T1D is an autoimmune disease that occurs when a child's body cannot produce insulin, and genetics as well as environmental factors play a role in the development of this disease. We propose to study the complex interplay of environmental, immunological and genetic factors to discover molecular signatures with a potential to advance clinical diagnosis and therapy at or before the onset of T1D.

描述（由申请人提供）：1型糖尿病（T1D）是一种自身免疫性疾病，其特征是胰岛素产生胰腺细胞功能的丧失，导致受影响个体中疾病的无数表现。当不进行治疗时，这可能导致死亡。许多研究表明，该疾病的发展是免疫，遗传和环境因素之间相互作用的结果。尽管已经涉及许多环境因素，但涉及参与或主要决定因素的机制尚未清楚地识别。已发表的研究表明，T1D是由作用于遗传易感个体的环境触发因素引起的，微生物感染及其免疫学后果被怀疑参与发病机理。已经提出了几种机制，以使微生物造成β细胞损伤。回顾性和前瞻性流行病学研究的数据强烈表明肠病毒参与T1D的发展。肠道微生物群中微生物多样性的改变已显示会引发异常的粘膜免疫反应，以进一步进一步T1D的进展。 T1D的遗传敏感性性状越来越多，包括HLA，胰岛素，蛋白酪氨酸磷酸酶-22，细胞毒性T-淋巴细胞相关蛋白4，白介素2受体和C-型肠蛋白的基因座。这种复杂性使它们作为预测测试不太理想。尽管众所周知，遗传敏感性基因在T1D的发展中起着重要作用，但细胞变化以及环境触发因素可能是出色的，潜在的普遍生物标志物来进行风险评估。在这项研究中，我们建议分析来自最近被诊断为T1D，其兄弟姐妹以及来自试验网络（www.diabetestrialnet.org）的儿童和青少年患者人群的血液，粪便和尿液样本。我们建议应用高通量基因组学，蛋白质组学和代谢组学技术来识别区分这些同胞的分子特征。通过对高分辨率分子数据的反卷积，我们期望鉴定蛋白质和代谢物的病毒 - 微生物特异性相关模式。我们的目的是从大量生物成分中发现和验证候选生物标志物。从基因组，蛋白质组学和代谢组数据集到宿主微生物组数据和基因型的相关性。我们的目的是通过应用新颖的分子方法来将疾病状态相关联，以早期诊断和预测T1D发作，从而为潜在的疗法或干预策略奠定了基础，来推进非侵入性临床测试。 公共卫生相关性：在过去的20年中，儿童和青少年的I型糖尿病（T1D）的发病率一直在迅速上升。 T1D是一种自身免疫性疾病，当孩子的身体无法产生胰岛素，遗传学以及环境因素在这种疾病的发展中起作用。我们建议研究环境，免疫学和遗传因素的复杂相互作用，以发现在T1D发作时或之前或之前或之前或之前，有可能进步临床诊断和治疗。