The mutant mouse strain C57BL/Ks-fat/fat is a new model for human obesity and noninsulin diabetes mellitus (NIDDM) with its age-related pathological complications. In addition to the """"""""maturity"""""""" onset of obesity and NIDDM, fat is the first animal model that exhibits human-like diabetic retinopathy, a major cause of blindness in the United States. In this grant, we propose to: 1) fine structure map the genomic region containing the fat gene and test four possible candidate genes for cosegregation with fat; 2) sequence a candidate gene from both mutant and normal mice if one of the candidate genes cosegregates with fat; and 3) if recombination events occur between fat and all four candidate genes, attempt to clone fat beginning at the two closest crossover events flanking the fat locus. Finding the mutations that cause obesity/diabetes syndromes in animal models is important because it allows elucidation of the molecular mechanisms of the disease process and because such mutations can serve as candidates for human studies. In addition, we will identify a genetic factor which protects fat/fat mice from diabetes. We propose to map this diabetes protective gene and select parents from diabetic and nondiabetic mice in order to create two congenic strains of mice: C57BL/Ks fat-normoglycemic and C57BL/Ks fat- hyperglycemic. The two strains will be characterized for feeding behavior, growth and obesity, plasma insulin, plasma glucose, and pancreatic histology. These two congenics will provide a valuable new animal resource for investigations into NIDDM, and allow investigators to determine whether high plasma insulin or high plasma glucose levels lead to the pathologies associated with NIDDM.
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