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.
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