The Diabetes Genome Anatomy Project (DGAP) represents a new initiative in unraveling the interface between insulin action; insulin resistance and the genetics of type II diabetes. The project was developed in conjunction with NIDDK and in response to the report of the Diabetes Research Working Group, and is presented in the form of a Bioengineering, Bioimaging, and Bioinformatics Research Partnership (BRP), representing the efforts of investigators from five institutions. There are six projects and four cores that form a highly interactive matrix and also serve as a scaffold on which to build future projects or interactions with related projects and grants. The overall goal of the project is to identify the sets of the genes and gene products involved in insulin action and the predisposition to type 2 diabetes, as well as the secondary changes in gene expression that occur in response to the metabolic abnormalities present in diabetes. There are five major and one pilot project involving human and rodent tissues that will allow us to: (1) Create a database of the genes expressed in insulin-responsive tissues, as well as accessible tissues such as lymphocytes, that are regulated by insulin, insulin resistance and diabetes. (2) Assess levels and patterns of gene expression in each tissue before and after insulin stimulation in normal and genetically-modified rodents; normal, insulin resistant and diabetic humans, and in cultured and freshly isolated cell models. (3) Correlate the level and patterns of expression at the mRNA and/or protein level with the genetic and metabolic phenotype of the animal or cell. (4) Generate genomic sequence from a panel of humans with type 2 diabetes focusing on the genes most highly regulated by insulin and diabetes to determine the range of sequence and expression variation in these genes and the proteins they encode, which might affect the risk of diabetes or insulin resistance. The resultant information will be used to create a highly annotated and interactive public database, standardized protocols for gene expression and proteomic analysis, and ultimately diabetes-specific and insulin action-specific DNA chips for investigators in the field. In this manner, we propose to define the normal anatomy of gene expression (i.e. basal levels of expression and response to insulin), the morbid anatomy of gene expression (i.e., the impact of diabetes on expression patters and the insulin response) and the extent to which genetic variability might contribute to the alterations in expression or to diabetes itself. This will aid all investigators in the quest to unravel the complexity of insulin action and its alterations in diabetes, and ultimately help develop more effective and specific modes for classification, metabolic staging and therapy of the disease.
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