PDX Core

PDX核心

• 批准号: 10733234
• 负责人: Nicolas Skuli
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733234
• 关键词: Academic Detailing; Address; Adoption; Affect; Animal Husbandry; Animals; BLT mice; Behavior; Bone Marrow; Caring; Cell physiology; Center for Translational Science Activities; Complex; Consultations; Core Facility; Decontamination; Development; Engraftment; Equipment; Growth; Growth Factor; Guidelines; Human; Human Resources; IL6 gene; Immunocompromised Host; Infection; Liver; Maintenance; Malignant Neoplasms; Methods; Modeling; Mouse Strains; Mus; Natural Killer Cells; Operative Surgical Procedures; Outcomes Research; Pennsylvania; Pilot Projects; Procedures; Productivity; Publications; Reproducibility; Research; Research Personnel; Running; Sterility; Thymus Gland; Tissue Banks; Tissue Harvesting; Tissues; Training; Transgenes; Transgenic Organisms; Transplantation; Universities; Xenograft procedure; animal care; cost; cytokine; education research; experimental study; fetal; human model; human tissue; laboratory experiment; leukemia; leukemia tissue bank; model development; mouse model; novel; patient derived xenograft model; programs; skills; stem cells; success

Summary: The PDX Core of the UP-PDTC is the primary experimental laboratory of the extensive xenotransplantation program at the University of Pennsylvania (UPENN). Research into human cancers is increasingly dependent on the transplantation of human tissues into highly immunocompromised mouse strains that allow various degrees of humanization. The number and type of these models continues to increase. Over the last few decades, researchers have developed models that lack T, B or NK cell function such as the NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG)[1], the similar NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) [2] as well as mice generated on this background with transgenes introduced to allow for expression of human growth factors or cytokines that can enhance the engraftment, growth or function of human tissues. In other cases, transplantation of multiple human tissues including fetal bone marrow, liver and thymus (BLT) allows for enhanced functionality of engrafted tissue using the so called BLT mouse model[3]. Although there is relatively little by way of detailed academic descriptions of the animal care requirements of these strains, multiple publications have demonstrated that these strains are prone to infections and that such infections can change engraftment of human tissues or behavior of human tissues after engraftment affecting experimental reproducibility and robustness [4-8]. Such infections can impact on outcome of research experiments and this lack of reproducibility combined with the high cost of maintaining these mouse strains has limited their adaptation and use. At UPENN, we have addressed this concern by developing a specific Core facility, the Stem Cell and Xenograft Core (SCXC), which is focused on maintenance of highly immunocompromised mouse strains and facilitating research. As shown below, we have had wide acceptance and increasing use of our expertise and facility with numerous researchers adapting patient-derived xenograft (PDX) models in particular. This success is due largely to a combination of an isolated vivarium suite, development of facility specific standard operating procedures, and highly skilled and trained personnel. UPENN has allowed us to adapt and utilize a 6 room suite in the Smilow Center for Translational Research Building. Access to and animal husbandry within this suite is controlled by our animal staff. All users must undergo training to access the SCXC animal suite and must adhere to strict sterility rules. The suite is maintained using frequent cleaning and decontamination of all equipment on a routine basis. Using this space and these guidelines, the animal use within the SCXC has increased to the point where we are providing 900 animals per month to users; space occupancy is currently running at 85% of predicted maximal capacity. Importantly, we anticipate continued growth of animal use as we have helped to create our own mouse strains using transgenic procedures performed within our suite, early adoption and characterization of unpublished mouse strains (NSG-IL6) and the anticipated arrival of complex mouse strains such as the MISTRG mouse[9, 10].

总结： UP-PDTC的PDX核心是广泛异种移植的主要实验室 宾夕法尼亚大学（UPENN）的一个项目。对人类癌症的研究越来越依赖于 将人体组织移植到高度免疫低下的小鼠品系中， 人性化的程度。这些模型的数量和类型继续增加。过去几 几十年来，研究人员已经开发出缺乏T、B或NK细胞功能的模型，如NOD。 Prkdcscid Il 2 rgtm 1 Wjl/SzJ（NSG）[1]，类似的NOD.Cg-Prkdcscid Il 2 rgtm 1 Sug/JicTac（NOG）[2]以及小鼠 在此背景下产生，引入转基因以允许表达人生长因子，或 可以增强人体组织的移植、生长或功能的细胞因子。在其他情况下，移植 包括胎儿骨髓、肝脏和胸腺（BLT）在内的多种人体组织的移植， 使用所谓的BLT小鼠模型移植组织[3]。虽然有相对较少的方式详细 关于这些菌株的动物护理要求的学术描述，多个出版物已经证明 这些菌株易于感染，并且这种感染可以改变人体组织的植入， 移植后人体组织的行为影响实验的重现性和稳健性[4-8]。等 感染会影响研究实验的结果，这种缺乏可重复性的情况， 维持这些小鼠品系的成本限制了它们的适应和使用。在UPENN，我们已经解决了 通过开发一个特定的核心设施，干细胞和异种移植核心（SCXC），这是重点关注 维持高度免疫受损的小鼠品系并促进研究。如下图所示，我们 我们的专业知识和设施得到了广泛的接受和越来越多的使用，许多研究人员正在适应 特别是患者来源的异种移植物（PDX）模型。这一成功主要归功于一个孤立的 动物园套件，制定设施特定的标准操作程序， 人员的UPENN允许我们适应和利用Smilow翻译中心的6间套房 研究大楼。该套房内的动物饲养和动物管理由我们的动物工作人员控制。所有用户 必须经过培训才能进入SCXC动物套房，并且必须遵守严格的无菌规则。套房 定期对所有设备进行频繁清洁和去污。利用该空间 根据这些指导方针，SCXC内的动物使用已经增加到我们提供900 动物每月向用户;空间占用目前运行在85%的预测最大容量。 重要的是，我们预计动物使用的持续增长，因为我们已经帮助创造了我们自己的小鼠品系 使用我们的套件内进行的转基因程序，早期采用和未发表的 小鼠品系（NSG-IL 6）和复杂小鼠品系如MISTRG小鼠的预期到达[9， 10]。