T1D:Investigating the Gut Microbiome, Urinary Proteome and Metabolome

描述(申请人提供)：1型糖尿病(T1D)是一种自身免疫性疾病，其特征是产生胰岛素的胰腺细胞功能丧失，导致患者出现多种疾病症状。如果不治疗，这可能会导致死亡。许多研究表明，该病的发展是免疫、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涉其中，但其参与机制或主要决定因素仍未明确。已发表的研究表明，T1D是作用于遗传易感个体的环境触发因素的结果，微生物感染及其免疫学后果被怀疑参与了发病机制。关于微生物对β细胞损伤的原因，已经提出了几种机制。回顾和前瞻性流行病学研究的数据强烈表明肠道病毒参与了T1D的发生。肠道微生物区系中微生物多样性的改变已被证明触发了异常的粘膜免疫反应，从而进一步促进了T1D的进展。T1D的遗传易感性特征越来越多，包括人类白细胞抗原、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。这种复杂性使它们作为预测性测试变得不那么可取。虽然已知遗传易感基因在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极好的、可能更通用的风险评估生物标记物。在这项研究中，我们建议分析来自TrialNet网络(www.DiabetesTrialNet.org)的最近被诊断为T1D的儿童和青少年患者及其兄弟姐妹和高危队列的血液、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队列的分子特征。通过高分辨率分子数据的反卷积，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。我们的目标是通过宿主微生物组数据和基因型的关联，从大量生物成分中发现和验证候选生物标记物；从基因组、蛋白质组和代谢组数据集中发现和验证候选生物标记物。我们的目的是通过应用新的分子方法来关联疾病状态以进行早期诊断和预测T1D的发病，从而推进非侵入性临床测试，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，儿童和青少年中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，发生在儿童身体不能产生胰岛素的时候，遗传和环境因素在这种疾病的发展中发挥了作用。我们建议研究环境、免疫学和遗传因素的复杂相互作用，以发现有可能在T1D发病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.