This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genetic, immunological, and exogenous factors interact to induce pancreatic beta-cells autoimmunity in a small minority of the individuals who have a genetic predisposition to developing insulin-dependent diabetes mellitus (IDDM). Our past studies proved that preclinical IDDM could be identified in children and adults with immune and metabolic markers. They also demonstrated that persistent production of autoantibodies against beta-cell antigens in high-risk individuals almost always commenced prior to the time of study enrollment. We therefore hypothesize that the initiation of the autoimmune cascade and the resultant molecular and cellular changes that culminate in clinical disease, occur in the very early years of life. Because it identifies babies at high risk for beta-cell autoimmunity prior to their earliest production of autoantibodies, our neonatal genetic screening program provides us with our first chance ever to test the hypothesis in a cohort design. We propose the following specific aims: 1) To identify newborn babies at increased risk for the development of IDDM from 3,000 (per year) at low risk in the general population and at higher risk among relatives of IDDM patients. Risk assessment using HLA and family history of diabetes will assign babies to five risk groups for the development of IDDM and autoantibodies: very high, high, moderate and low risk and protective groups. We will also explore the exogenous factors (viruses, diet, etc.) that may trigger or modify the autoimmune process. 2) To determine the precise timing and sequence of the appearance of autoantibodies. We will test GAD, IAA, ICA, IA2, and IA2? at 6, 12, and 18 months and then at one-year intervals for all high/moderate risk subjects and a sample of low risk controls. 3) To study the interaction of antigen presenting cells, T cells and susceptibility genes in the immunopathogenesis of diabetes. Specifically we will determine expression levels of macrophage-derived prostaglandin synthase 2 (PGS2). 4) To identify specific molecular changes associated with disease progression by quantitative analyses of gene expression using DNA chips and microarray technologies. The most promising candidate genes will be further characterized in longitudinal samples using other techniques more suitable for large-scale studies. 5) To improve participation and retention rates for the study, we will assess the psychological impact of diabetes screening on family members. Since our new program will explore a previously inaccessible pre-clinical phase of IDDM, our studies should provide novel insights that may advance new genetic and immunologic technologies for predicting and preventing the disease.
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