MOUSE MODELING AND ANIMAL DEVELOPMENT

项目总结(见说明)： CORE C(小鼠建模和动物发展核心)将为项目1-4所述的生物和治疗评估研究的野生型和突变小鼠品系和疾病模型的产生和维护提供全面支持。内部生成的转基因小鼠品系允许我们定制小鼠模型的设计，以满足项目的特定需求。 维护和繁育服务将提供最有效和最具成本效益的手段，以产生、维护和分发项目所需的多种品系的老鼠。我们为P01应用计划的绝大多数治疗试验都是在小鼠模型上进行临床前试验。因此，需要及时获得足够数量的这些专门菌株，以充分服务于各种协作的临床前项目，这些项目对于推进患者的早期临床测试至关重要。因此，该核心将积极参与新转基因和基因靶向小鼠模型的产生和表征，这将促进每个项目的科学目标。核心C的具体目标是1)培育和鉴定抗体和细胞因子介导的治疗评估的转基因或基因敲除模型；2)建立异种移植模型，包括EBV+B细胞淋巴瘤的人-PBL-SCID小鼠模型，播散性白血病、淋巴瘤和实体瘤的同基因和异种模型，以及产生有条件的基因敲除模型；3)集中小鼠订购、繁殖、维护和分配；4)根据需要为每个项目提供专业服务。小鼠模型的拟议使用将为项目1的疾病发病机制、药物作用机制和治疗效果提供新的见解；在体内验证项目2中单核和巨噬细胞FcyR信号的负调控；项目3中对NK细胞发育、耐受性和抗体依赖性细胞毒性的功能的评估；以及项目4中髓系来源的抑制细胞与其他先天免疫效应细胞的相互作用。因此，核心C将通过促进转基因、基因敲除、异种移植和其他小鼠模型在翻译研究中的开发，形成该计划拨款计划的组成部分。

PROJECT SUMMARY (See instructions): 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.