T1D:Investigating the Gut Microbiome, Urinary Proteome and Metabolome

描述（由申请人提供）：1型糖尿病（T1 D）是一种自身免疫性疾病，其特征在于产生胰岛素的胰腺细胞的功能丧失，导致受影响个体中疾病的多种表现。如果不治疗，可能导致死亡。许多研究表明，该病的发生是免疫、遗传和环境因素相互作用的结果。虽然，许多环境因素已经牵连，参与的机制或主要的决定因素尚未明确确定。已发表的研究表明，T1 D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后果被怀疑参与了发病机制。已经提出了微生物导致β细胞损伤的几种机制。回顾性和前瞻性流行病学研究的数据强烈表明肠道病毒参与T1 D的发展。肠道微生物群中改变的微生物多样性已被证明会引发异常的粘膜免疫反应，从而进一步促进T1 D的进展。T1 D的遗传易感性性状变得越来越多，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、白细胞介素-2受体和C型凝集素的基因座。这种复杂性使得它们不太适合作为预测性测试。虽然已知遗传易感基因在T1 D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风险评估的优秀，可能更通用的生物标志物。在这项研究中，我们建议分析来自TrialNet网络（www.diabetestrialnet.org）最近被诊断患有T1 D的儿童和青少年患者人群及其兄弟姐妹和高危人群的血液，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群体的分子特征。通过对高分辨率分子数据的去卷积，我们期望识别蛋白质和代谢物的病毒-微生物特异性相关模式。我们的目标是从大量的生物成分中发现和验证候选生物标志物;通过宿主微生物组数据和基因型的相关性，从基因组，蛋白质组和代谢组数据集。我们的目的是通过应用新的分子方法来推进非侵入性临床检测，以关联疾病状态，从而早期诊断和预测T1 D发作，为潜在的治疗或干预策略奠定基础。 公共卫生相关性：在过去20年中，儿童和青少年I型糖尿病（T1 D）的发病率迅速上升。T1 D是一种自身免疫性疾病，当儿童的身体不能产生胰岛素时就会发生，遗传和环境因素在这种疾病的发展中发挥作用。我们建议研究环境，免疫和遗传因素的复杂相互作用，以发现有可能在T1 D发作时或之前推进临床诊断和治疗的分子特征。

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.