Core C (Mouse Modeling and Animal Development Core) will provide comprehensive support for generation and maintenance of wild type and mutant mouse strains and disease models for biological and therapeutic evaluation studies described in Projects 1-4. In-house generation of genetically altered mouse strains allows us to customize the design of mouse models to meet the specific needs of the Projects. Maintenance and breeding services will provide the most efficient and cost effective means of generating, maintaining, and distributing the multiple strains of mice needed for the Projects. The vast majority of our therapeutic trials planned for this P01 application are preceded by preclinical experimentation in mouse models. Thus, timely access to adequate numbers of these specialized strains is needed to adequately service the variety of collaborative pre-clinical projects that are essential for advancement to early stage clinical testing in patients. The core will therefore be actively involved in generation and characterization of novel transgenic and gene targeted mouse models that will facilitate the scientific goals of each of the Projects.
The specific aims of the Core C are 1) Breeding and characterization of transgenic or knockout models for antibody and cytokine mediated therapeutic evaluation; 2) Generation of xenograft models including a human-PBL-SCID mouse model with EBV+ B cell lymphoma, syngeneic and xenogeneic models of disseminated leukemia, lymphoma and solid tumors and the generation of conditional knock-out models; 3) Centralized mouse ordering, breeding, maintenance and distribution; 4) Specialized services to each Projects as warranted. The proposed use of mouse models should provide new insights into disease pathogenesis, drug mechanism of action, and therapeutic efficacy of targeted agents for Project 1; in vivo validation of negative regulators of monocyte and macrophage FcyR signaling for Project 2; assessment of NK cell development, tolerance, and function in antibody dependent cellular cytotoxicity in Project 3; and the interaction of myeloid derived suppressor cells with other innate immune effector cells in Project 4. Thus, the Core C will form an integral part of this Program Project Grant by facilitating exploitation of transgenic, knockout, xenograft and other mouse models in translational research.
Relevance; The Core C will enable all investigators on this Program Project to have access to a centralized and integrated mouse facility. Genetically engineered animal models often require specialized care and close monitoring by investigators to identify and maintain the needed phenotypes. Timeliness in serving the integrated Program Project is of paramount importance, especially in testing preclinical and clinical immune models. These issues, combined with the difficulty from a regulatory and physical standpoint for animals to travel between vivarium facilities, make it essential that investigators be provided with immediate access to needed mouse resources in a centralized facility.
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