Consortium for Identification of Environmental Triggers*

描述(由申请人提供)： 了解诱导胰腺β细胞自身免疫并允许其进展为1型糖尿病(T1D)的基因、免疫反应和环境因素之间的相互作用，需要进行前瞻性监测的大量队列研究。我们假设，自身免疫级联以及最终导致胰岛素缺乏的分子和细胞变化，是由生命早期的环境因素启动/触发的。由于缺乏大量合适的队列，这些诱因的确定受到了阻碍。包括DAISY、DIPP和我们自己的大熊猫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和阐明免疫发病机制。建立一个联合体将允许采取协调的、多学科的方法，以标准化的方式收集信息和样本，比较小的独立调查具有更大的统计权力，并为随后的基于假设的研究建立一个数据和生物样本的中央储存库。作为该联盟的一部分，这家拟议的MCG/UF临床中心有以下具体目标：1)在未来五年内，从普通人群中招募20,000名新生儿和2,000名有一级糖尿病亲属的新生儿/婴儿(&lt；3个月大)。将确定人类白细胞抗原-DQB1和DRB1基因型别以进行风险评估。2)监测高危儿童向β细胞自身免疫和临床糖尿病的进展，并在每次随访时收集生物标本，包括血清、外周血淋巴细胞RNA、粪便和尿样。3)确定/确认1型糖尿病的环境诱因。我们将进行问卷指导访谈，并进行儿童早期饮食摄入量分析。我们还将寻求确认肠道病毒等候选感染源的作用，并利用新的高功率技术发现新的候选触发因素，如红细胞膜上的脂肪酸水平和化学毒素。这项应用的长期目标是识别在遗传易感人群中引发1型糖尿病发展的环境因素或预防这种疾病的环境因素。识别这些因素将有助于更好地了解疾病的发病机制，并制定新的预防/延迟或逆转疾病的策略。

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.