Name of the inventor: Domenico Accili Problem or Unmet Need: Type II diabetes is a very complex disease involving many tissues and several key protein components, two of which are insulin receptor and the transcription factor FoxO1. Recently, FoxO1 was...

Name of the inventor: Domenico Accili Problem or Unmet Need: Type II diabetes is a very complex disease involving many tissues and several key protein components, two of which are insulin receptor and the transcription factor FoxO1. Recently, FoxO1 was determined metabolically as the insulin-regulated transcription factor responsible for insulin action on gene regulation. For this role, FoxO1 is a prime target for drug discovery. In order to study and model the effects of drug action upon FoxO1, knockout mouse lines would be of great benefit. Unfortunately, the FoxO1 knockout mouse is embryonic lethal. As for the insulin receptor, knockout and null mutation mouse lines have advanced the understanding of the pathogenesis of insulin sensitivity. However, these results are different than the mutations found in humans. Details of the Invention: The lead inventor has generated several lines of different genetically altered mice that aid in researching the role of glucose production and insulin resistance in vivo. In one mouse line, the FoxO1 gene can be conditionally ablated in as tissue-specific, developmental stage-specific, or a combined manner using the Cre-lox method of selection. By crossing these lines with mice expressing Cre under a promoter of interest, FoxO1 can be removed and the affects studied. In another mouse line, FoxO1 has been only allowed to be expressed in liver, pancreatic b-cells, and choroids plexus tissues. This generates a means to control glucose production by the liver as well as pancreatic b-cell proliferation, both important in modeling diabetes. In a third mouse line, insulin receptor has been conditionally expressed only in liver, pancreatic b-cells, and choroids plexus tissues. This aids in the modeling and investigation of insulin resistance in muscle and adipose tissue. Applications: • Generation of conditional ablations in mice of the FoxO1 gene in a tissue specific manner • Generation of conditional ablations in mice of the FoxO1 gene in a developmental stage manner • Transgenic mouse lines that aid in the evaluation of the role of FoxO1 in only the liver, pancreatic b-cells, and choroids plexus. • Transgenic mouse lines that aid in the interpretation of the role of the insulin receptor in only the liver, pancreatic b-cells, and choroids plexus. • Transgenic mouse lines to aid in determining drug action along the FoxO1 and the insulin receptor pathways. • Transgenic mouse lines to aid in investigation of insulin resistance in muscle and adipose tissue. Advantages: • Ability to control glucose production by the liver • Ability to control pancreatic b-cell proliferation • A more precise metabolic phenotype of insulin resistance in muscle and adipose tissue • Mouse lines that survive longer than previous knockouts • Ability to control manipulations of FoxO1 expression in a tissue-specific manner • Ability to control manipulations of FoxO1 expression in a developmental-stage manner

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