Consortium for Identification of Environmental Triggers*

描述（由申请人提供）： 了解诱导胰腺β细胞自身免疫并使其进展为1型糖尿病（T1 D）的基因，免疫反应和环境因素的相互作用需要前瞻性监测的大型队列。我们假设，自身免疫级联反应和由此产生的分子和细胞的变化，最终导致胰岛素缺乏症，是由环境因素在生命的最初几年启动/触发。由于缺乏大量合适的队列，这些触发因素的确定受到阻碍。包括DAISY、DIPP和我们自己的PANDA在内的几项前瞻性研究旨在建立队列，以识别环境触发因素并阐明免疫发病机制。建立一个联合体将有助于采取协调一致的多学科办法，以标准化方式收集信息和样本，比小型独立调查所能达到的统计能力更强，并为随后的基于假设的研究建立一个数据和生物样本中央储存库。作为联盟的一部分，该拟议的MCG/UF临床中心具有以下具体目标：1）在未来五年内从普通人群中招募20，000名新生儿和2，000名新生儿/婴儿（<3个月），这些新生儿/婴儿有一级糖尿病亲属。将确定HLA-DQB 1和DRB 1基因型以进行风险评估。2)监测高危儿童β细胞自身免疫和临床糖尿病的进展，并在每次随访时采集生物标本，包括血清、外周血淋巴细胞RNA、粪便和尿液样本。3)识别/确认1型糖尿病的环境触发因素。我们将进行指导性访谈，并进行幼儿饮食摄入量分析。我们还将寻求确认候选感染因子（如肠道病毒）的作用，并使用新型高功率技术发现新的候选触发因子，如红细胞膜上的脂肪酸水平和化学毒素。本申请的长期目标是鉴定在遗传易感个体中引发1型糖尿病发展或保护免于该疾病的环境因素。这些因素的识别将导致更好地了解疾病的发病机制和新的战略，以预防/延迟或扭转疾病。

DESCRIPTION (provided by applicant): Understanding of the interactions of genes, immune responses, and environmental factors that induce pancreatic beta-cell autoimmunity and allow its progression to type 1 diabetes (T1D) requires a large cohort that is prospectively monitored. We hypothesize that the autoimmune cascade and the resultant molecular and cellular changes that culminate in insulin deficiency, are initiated/triggered by environmental factors in the very early years of life. The identification of these triggers has been hampered by the lack of large suitable cohorts. Several prospective studies including DAISY, DIPP and our own PANDA have aimed at establishing cohorts for the identification of environmental triggers and elucidation of the immunopathogenesis. The creation of a consortium will allow for a coordinated, multi-disciplinary approach, the collection of information and samples in a standardized manner, greater statistical power than can be achieved in smaller independent investigations, and the creation of a central repository of data and biologic samples for subsequent hypothesis-based research. This proposed MCG/UF clinical center as part of the consortium has the following specific aims: 1) To recruit 20,000 newborns from the general population and 2,000 newborns/infants (<3 months of age) with 1st degree diabetic relatives during the next five years. HLA-DQB1 and DRB1 genotypes will be determined for risk assessment. 2) To monitor the progression to beta cell autoimmunity and clinical diabetes in high-risk children and to collect biological specimens including serum, peripheral blood lymphocyte RNA, stool and urine samples on every follow-up visit. 3) To identify/confirm environmental triggers for type 1 diabetes. We will conduct questionnaire-guided interviews and carry out early childhood dietary intake analysis. We will also seek to confirm the roles of candidate infectious agents such as enterovirus and discover new candidate triggers such as fatty acid levels on erythrocyte membranes and chemical toxins using novel high power technologies. The long-term goal of this application is the identification of environmental factors which trigger development of type 1 diabetes in genetically susceptible individuals or which protect against the disease. Identification of such factors will lead to a better understanding of disease pathogenesis and new strategies to prevent/delay or reverse the disease.