MOUSE MODELING AND ANIMAL DEVELOPMENT

项目总结（见说明）： 核心C（小鼠建模和动物发育核心）将为项目1-4中描述的生物学和治疗评价研究的野生型和突变型小鼠品系和疾病模型的生成和维护提供全面支持。内部产生的转基因小鼠品系使我们能够定制小鼠模型的设计，以满足项目的特定需求。 维护和繁殖服务将提供最有效和最具成本效益的方法来生产、维护和分发项目所需的多种小鼠品系。我们为P01应用计划的绝大多数治疗试验都是在小鼠模型中进行临床前实验。因此，需要及时获得足够数量的这些专门菌株，以充分服务于各种合作的临床前项目，这些项目对于推进患者的早期临床试验至关重要。因此，核心将积极参与新型转基因和基因靶向小鼠模型的生成和表征，这将促进每个项目的科学目标。核心C的具体目标是1）用于抗体和细胞因子介导的治疗评价的转基因或敲除模型的育种和表征; 2）异种移植模型的生成，包括具有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，以及条件性敲除模型的生成; 3）集中订购、饲养、维护和配送; 4）根据需要为每个项目提供专业服务。提出的小鼠模型的使用应该为项目1提供对疾病发病机理、药物作用机制和靶向剂的治疗功效的新见解;为项目2提供对单核细胞和巨噬细胞Fc γ R信号传导的负调节剂的体内验证;在项目3中评估NK细胞发育、耐受性和抗体依赖性细胞毒性中的功能;以及项目4中髓源性抑制细胞与其他先天性免疫效应细胞的相互作用。因此，核心C将通过促进转化研究中转基因、敲除、异种移植和其他小鼠模型的开发，成为该计划项目资助的一个组成部分。

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.