Large-scale mouse gene targeting projects, such as KOMP, EUCOMM, NorCOMM, and TIGM (collectively, the IKMC), have delivered a vast number of conditional-ready loxP-flanked alleles to the scientific community. Many of these are now available thanks to the efforts of programs such as KOMP2 to turn these stem cell resources into live mice. When combined with a Cre allele, this system allows investigators to interrogate gene function through precise deletion in a temporally specific and tissue specific manner. To capitalize on this IKMC resource will require that a large, diverse set of well-characterized Cre driver lines are available to researchers around the world. Unfortunately, at present, most existing Cre driver mouse strains are not available from public repositories and until recently, there was no single database that proposed to house comprehensive information about the functionality of Cre driver strains available to the scientific community. While the catalog of available strains has grown in recent years, there are still significant gaps that limit our ability to dissect gene function in certain tissue types. Moreover, despite the best efforts of those developing new Cre lines, the fidelity of Cre activity is not always ideal. Many difficulties have been reported in various Cre lines, including mosaic or incomplete deletion in a target tissue/cell type, inconsistent activity, expression in non-target tissues, and/or Cre-related toxicity. Frequently, these data are not reported or available to the potential user, and our work over the past several years has shown that a majority of Cre lines display off target activity. The overall goal of this project is to develop and distribute comprehensive Cre strain resources and information to the scientific community. The new resources will build upon the success of the Jackson Laboratory (JAX) Cre Repository, which includes both distribution and extended characterization of Cre driver lines, and the CrePortal, which leverages the informatics infrastructure of Mouse Genome Informatics to provide a database of Cre driver strains and their functionality. To complement these resources, this proposal also seeks to generate an expanded set of Cre driver strains that will fill gaps in our collection and potentially replace critical strains that are confounded by off target activity. Together, these will provide the community with a comprehensive source of Cre driver tool strains and information about them.
The mouse is an invaluable tool for modeling human disease. The tremendous power of the mouse is due in part to our ability to manipulate its genome in a precise manner. This proposal seeks to leverage our mouse and informatic resources to enhance the value of mouse tool strains for the scientific community. Because of our position as a central resource utilized by thousands of scientists around the world, this project promises to have an important impact on the development of new models of human disease.
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