Core 3: Mouse Models Core (MM Core)

项目总结-核心3：小鼠模型核心 Mouse Models Core（MM Core）将提供必要的增值服务，以支持所有P01项目。 由于所有项目都提出了用小鼠模型进行临床前实验性治疗试验，这些试验将受益于 专家专业人员，统一的程序和标准化的成像协议将使 比较P01的治疗方案，并确保所有治疗方案的可靠性、重现性和一致性。 建议的研究。为了支持这些目标，MM核心有三个具体目标。MM核心的首要目标 是提供小鼠和人体材料原位移植服务， 特定区域的脆弱性MM Core将移植小鼠和人类胰腺癌 类器官能够分析内在和获得性抗性，并测试克服抗性的新策略。 这些挑战在历史上限制了长期治疗的成功。MM Core将使用原位 1）测定HDAC抑制与DNA损伤剂协同作用的能力，重编程 成纤维细胞异质性，并增强对免疫治疗的反应（项目1），2）评估LIF的影响 和STAT 3缺失对肿瘤生长的影响（项目2），和3）确定 CA-19-9水平影响自噬（项目3）。MM核心的第二个目标是提供访问 在KPC本地模型中产生足够的肿瘤，以进行最有希望的生存研究。 在每个研究项目中确定的药物组合方案。KPC模型具有挑战性，因为小鼠必须 进行繁殖和基因分型，然后必须在适当和可重复的时间招募肿瘤动物 点使用超声成像来评估肿瘤大小。MM核心将使KPC模型能够用于 受益于具有注册所需专业诊断技术专业知识的专职人员的方式 肿瘤在5-8 mm之间的动物。这将确保生存所需的饲养的一致性 问题研究为了最大限度地减少所需动物的数量和产生的成本， 将用于KPC生存研究，将基于对所有原位移植数据的评价， 与EAB协商的项目领导。在KPC中显示出显著生存获益的药物组合 然后将在第二次试验中对模型进行评估，以确保重现性。第三个目标是提供 获得导管内注射病毒Cre以在编码复杂等位基因的小鼠中产生胰腺特异性缺失 组合。这种独特而苛刻的技术将由核心进行优化，以实现一致性， 再现性在其他应用中，该程序将在项目3中广泛使用，以描述 AMPK和ULK 1/2在肿瘤发生中的作用。综上所述，MM Core将提供可靠的、可重复的、 提供高质量的服务，并提供研究肿瘤细胞和肿瘤所需的技术。 使用移植物和本地小鼠模型和超声成像的微环境。

PROJECT SUMMARY – Core 3: Mouse Models Core The Mouse Models Core (MM Core) will provide essential, value-added services in support of all P01 projects. As all projects propose preclinical experimental therapeutic trials with murine models, such trials will benefit from expert professional staff where uniform procedures and standardized imaging protocols would enable comparison of therapeutic regimens across the P01 and ensure reliability, reproducibility, and consistency of all proposed studies. In support of these goals, the MM Core has three Specific Aims. The First Aim of the MM Core is to provide orthotopic transplantation services of mouse and human material, which will be used to identify cell compartment-specific vulnerabilities. The MM Core will transplant mouse and human pancreatic cancer organoids to enable analyses of intrinsic and acquired resistance, and to test new strategies for overcoming these challenges that have historically limited long-term therapeutic successes. The MM Core will use orthotopic transplantation to: 1) determine the ability of HDAC inhibition to synergize with DNA damaging agents, reprogram fibroblast heterogeneity, and potentiate the response to immunotherapy (Project 1), 2) assess the impact of LIF and STAT3 loss in the tumor microenvironment on tumor growth (Project 2), and 3) determine the extent to which CA-19-9 levels affect autophagy (Project 3). The Second Aim of the MM Core is to provide access to enough tumors generated in the KPC autochthonous model to perform survival studies on the most promising drug combination regimens identified in each Research Project. The KPC model is challenging, as the mice must be bred and genotyped, and then animals with tumors must be enrolled at appropriate and reproducible time points using ultrasound imaging to assess tumor size. The MM Core will enable the KPC model to be used in a way that benefits from a dedicated staff with expertise in the specialized diagnostic techniques required to enroll animals harboring tumors between 5-8 mm. This will ensure consistency in the husbandry needed for survival studies. To minimize the number of animals required, and costs incurred, decisions on which drug combinations will be used for KPC survival studies will be based on evaluation of all orthotopic transplantation data by the Project Leads in consultation with the EAB. Drug combinations showing significant survival benefit in the KPC model will then be evaluated in a second trial to ensure reproducibility. The Third Aim is designed to provide access to intraductal injection of viral Cre to create pancreas-specific deletions in mice encoding complex allele combinations. This unique and demanding technique will be optimized by the Core to achieve uniformity and reproducibility. Among other applications, this procedure will be used extensively in Project 3 to delineate the role of AMPK and ULK1/2 in tumorigenesis. Taken together, the MM Core will provide reliable, reproducible, high-quality services and provide access to the techniques required to study tumor cells and the tumor microenvironment using transplants and autochthonous mouse models and ultrasound imaging.