Understanding of the interactions of genes, immune responses, and environmental factors that induce pancreatic and allow its progression to type 1 diabetes (T1D) requires that the pathogenic process be identified from its onset. We hypothesize that the initiation of the autoimmune cascade and the resultant molecular and cellular changes that culminate in insulin deficiency, occur in the very early years of life. Only recently with the advent of high throughput genotyping technologies has the hypothesis become testable. In the first 4 years of our prospective assessment in newborns for diabetes autoimmunity (PANDA), we have screened >8,000 newborns from the general population and followed a cohort of ~300 high-risk infants whose HLA genotype puts them at high risk for developing diabetes. In addition, we have screened ~800 relatives of T1D-affected patients and are closely following 415 of them with high/moderate risk HLA genotypes. We seek to further define our preliminary findings of genetic, immunological, and environmental factors that may contribute to T1D pathogenesis. We propose four specific aims: 1) Expand to 23,000, the number of newborns screened from the general population and increase to 2,500, the number of HLA-typed relatives of T1D patients. 2) Monitor the appearance of beta cell autoimmunity (BCA) and its progression to T1D in children with high-risk genotypes, specifically examining the frequency, timing and order of appearance of Ab (GAD, IA2, IAA & ICA) beginning at 6 months of age and then at regular intervals (3-6 months) thereafter. We will also conduct questionnaire-guided interviews to collect detailed data on demographics, family history of autoimmunity, prenatal and neonatal exposures, infant diet, daycare, psychological stressors, and immunization to assess the impact of potential environmental factors, which may trigger or modify the autoimmune process. 3) Investigate the roles of pro-inflammatory prostaglandins on BCA. We will study the natural history of prostaglandin synthase-2 (PGS2) expression by monocytes, assess its predictive value for B-cell autoimmunity, and will seek confirmation of the observed association between a modulator of PGS-2 activity - dietary n-3 polyunsaturated fatty acids - and BCA by analyzing erythrocyte membrane fatty acid levels in Ab+ subjects and matched controls. 4) One of our novel and exciting findings derived from the high throughput microarray technology is the unique expression profiles of some 200 genes that associate with serum Ab positivity. This high-risk profile also occurs in ~25% of children under 3 years old who are Ab-, but who are HLA-DR3/4 and have a relative with T1D. This rate approximates the lifetime diabetes risk of these children. We now seek validation of the observed association in additional subjects after longer follow-up and we will determine the utility (specificity and sensitivity) of RNA profiling for prediction of BCA and T1D. Since our new program will explore a previously inaccessible pre-clinical phase of T1D, our studies should provide novel insights that may advance new genetic and immunologic technologies for predicting and preventing the disease.
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