Xenotransplant and Genome Editing Core

摘要 转基因和免疫功能低下的动物是研究免疫缺陷的金标准模型。 在正常发育和疾病的背景下造血细胞的分子调节，以及 开发用于多种非恶性血液病的新型基于干细胞的治疗方式 紊乱血液学研究的未来还在于我们能够在体外检测造血细胞功能， 单细胞水平以及将单细胞行为与转录组和表观遗传谱相关联。CCCEH 异种移植和基因组编辑核心（XGEC）是一个成熟的，富有成效的和创新的核心 旨在提供专门的小鼠品系，各种动物服务的效率和 标准化的细胞移植试验和转基因动物服务，及时和具有成本效益 向CCHSCC的成员展示时尚。总体假设是，一个集中的核心服务提供 CCHSCC成员的无数鼠标需求将提高有效性，及时性，成本效益和 科学研究的整体影响，从而加速血液病的发现和治疗。 疾病 与外部供应商相比，XGEC以具有成本效益的方式提供专门的小鼠品系， 包括免疫缺陷小鼠品系的集合（即，NSG、NSG-3GM 3、NRG-SGM 3、Rag-/-gc-/- /WvWv和B6.BoyJ）用于临床前研究的人造血细胞的异种移植 关于人和小鼠造血干细胞中的基因转移，对于人造血干细胞 和单细胞移植研究，以及定量（竞争性）造血干细胞移植 研究（目标1）。XGEC还提供专门的动物服务，允许人口和单细胞 移植试验，包括动物辐照和细胞移植服务（目标2），以及动物 操纵和监测服务（目标3）。此外，XGEC还提供生成的所有服务 转基因和遗传修饰的小鼠系（目标4）。自从它开始提供CRISPR-Cas服务以来， 2014年3月，核心已经产生了工程动物模型，以CCHMC的研究人员和之间 中心和更广泛的研究社区。最后，XGEC提供技术支持， 研究合作，全面设计和分析体内研究（目标5）。这些服务将 促进参与CCCEH的研究者之间的专业知识共享和互动， 并将在未来吸引新的核心用户。总的来说，XGEC提供独特的动物服务组合， 在Starczynowski博士的监督下， 和黄在一个成本效益和标准化的方式，从而提供国家的最先进的调查非- 恶性分子血液学这些服务将支持开发新的治疗方式 （药理学和基于细胞的）和转化I期和II期研究。

Abstract Genetically modified and immunocompromised animals are the gold-standard models for investigating the molecular regulation of hematopoietic cells in the context of normal development and diseases, and for the development of novel stem cell-based therapeutic modalities for a wide variety of non-malignant hematological disorders. The future of hematology research also lies in our ability to examine hematopoietic cell function at single cell level and correlate single cell behavior with transcriptome and epigenetic profiling. The CCCEH Xenotransplant and Genome Editing Core (XGEC) is an established, productive and innovative core designed to provide specialized mouse strains, a wide variety of animal services for efficiency and standardization of cell transplantation assays, and transgenic animal services in a timely and cost effective fashion to members of the CCHSCC. The overarching hypothesis is that a centralized core service providing the myriad mouse needs of CCHSCC members will enhance the effectiveness, timeliness, cost-efficiency and overall impact of the scientific research and thereby accelerate the discovery and treatment of hematological diseases. XGEC provides specialized mouse strains in a cost effective manner compared with external vendors, including a collection of immunodeficient mouse strains (i.e., NSG, NSG-3GM3, NRG-SGM3, Rag-/-gc-/- /WvWv, and B6.BoyJ) utilized for xenotransplantation of human hematopoietic cells, for preclinical studies concerning gene transfer in humans and mouse hematopoietic stem cells, for human hematopoietic stem cell and single cell engraftment studies, and for quantitative (competitive) hematopoietic stem cell engraftment studies (Aim 1). The XGEC further provides specialized animal services allowing for population and single cell transplantation assays, including animal irradiation and cell transplantation services (Aim 2), and animal manipulation and monitoring services (Aim 3). In addition, the XGEC offers all services for the generation of transgenic and genetically–modified mouse lines (Aim 4). Since it began offering CRISPR-Cas services in March 2014, the core has already generated engineered animal models to CCHMC investigators and among Centers and within the wider research community. Lastly, XGEC provides technical support and facilitates research collaborations for comprehensive design and analysis of in vivo studies (Aim 5). These services will facilitate the sharing of expertise and promote interaction between investigators participating in the CCCEH, and will attract new core users in the future. Overall, the XGEC offers a unique combination of animal services and concentrated expertise performed by well-trained personnel under the supervision of Drs. Starczynowski and Huang in a cost effective and standardized way, thereby providing state-of-the-art investigation of non- malignant molecular hematology. These services will support the development of new therapeutic modalities (pharmacological and cell-based) and translational Phase I and II studies.