IMMUNOPATHOGENESIS OF DIABETES--STUDIES IN INFANTS

Project: Research project

Project Details

Description

DESCRIPTION (adapted from applicant's abstract): 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 IDDM. Previous studies have proven that preclinical IDDM can be
identified in children and adults with immune and metabolic markers. It has
been demonstrated that persistent production of autoantibodies against (beta)-
cell antigens in high-risk individuals almost always commenced prior to the
time of study enrollment. It led into the hypothesis 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, the neonatal genetic screening program
provides investigator the first chance ever to test the hypothesis in a cohort
design. The following specific aims are proposed: (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. To improve
participation and retention rates for the study, the psychological impact of
diabetes screening on family members and the effects of exogenous factors
(viruses, diet, etc.) that may trigger or modify the autoimmune process will
be studied; (2) to determine the precise timing and sequence of the appearance
of autoantibodies, GAD, IAA, ICA, IA2(beta) 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 will be tested; (3) to study the interaction of antigen
presenting cells, T cells and susceptibility genes in the Immunopathogenesis
of diabetes, the expression levels of macrophage-derived PGS2 and Th1/Th2-
associated cytokines (IL-4 and IFN-gamma) in longitudinal samples from high
and low-risk subjects will be determined. Principle investigator will also
determine whether endogenous retrovirus RNA expression in peripheral blood is
altered in subjects who develop (beta)-cell autoimmunity; and (4) to identify
specific molecular changes associated with disease progression by quantitative
analyses of gene expression using DNAchips and microarray technologies. The
most promising candidate genes will be further characterized in longitudinal
samples using other techniques more suitable for large-scale studies. Since
new program will explore a previously inaccessible preclinical phase of IDDM,
the present studies should provide novel insights that may advance new genetic
and immunologic technologies for predicting and preventing the disease.
StatusFinished
Effective start/end date9/7/996/30/09

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $697,687.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $718,614.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $722,780.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $677,195.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $670,401.00

ASJC

  • Medicine(all)

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