The Core C (Mouse modeling and animal development core) will provide a comprehensive supportive role for generation and maintenance of mutant mouse strains and disease models for the evaluation of the therapeutic agents described in projects 1,2,3and 4. Custom designed generation of novel mouse models will meet the specific needs of each of the projects. In-house mouse model generation, breeding and maintenance will provide the most efficient means of making the rare mutant mouse strains available to meet the specific needs of the projects contained within this program application. Ready access to adequate numbers of these specialized strains is needed to maintain the significant integration of the variety ofpre- clinical, clinical and biological projects for the generation of research results in a timely fashion. All four projects in this program project application make use of normal and/or mutant mice of various strains. Transgenic and gene-targeted mice are essential tools in this research program, and a mouse core is the most efficient and cost-effective way to supply these invaluable animal resources to the number of investigators involved in a coordinated timely fashion. The core has been 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. Importantly, several gene targeted mutant strains need to be backcrossed onto various backgrounds for the unique needs of specific projects. The animal breeding and maintenance core is created to satisfy the needs for model generation, purchase, maintenance, breeding, and genotyping for each of the projects to facilitate overall success of the program project. The specific goals of the Core C will be 1) Breeding of novel transgenic and/or knockout mouse models for antibody and cytokine mediated therapeutic evaluation 2) Generation of hu-PBL xenograft models in SCID mice to study human innate immune mechanisms 3) Centralized mouse ordering, breeding, maintenance and distribution 4)Specialized needbasedservices to each of the projects. The contribution of the Core C is reflected in the 31 peer reviewed publications using transgenic and/or targeted mutant mouse strains during the previous funding cycle. The proposed services of the Core C will provide critical insights into therapeutic efficacy, mechanistic studies, and strategies to improve antibody mediated cellular cytotoxicity of both novel promising experimental small modular irnmuno Pharmaceuticals such as CD37-SMIP) and therapeutic antibodies currently in clinic such as Rituximab and Herceptin mediated therapy (Project 1,2,4), mechanisms of FcR signaling (Projects 1 and 2), cytokine signaling (Project 3 and 4) and NK cell development and function (Project 3 and 4). Thus the Core C will form an integral part of this program project by facilitating exploitation of transgenic, knockout and hu-PBL xenograft mouse models in """"""""Mouse- >human ->Mouse->human"""""""" translationalresearch.
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