Core 3: Mouse Models Core (MM Core)

核心 3：鼠标模型核心（MM 核心）

基本信息

批准号：
10629069
负责人：
Geoffrey Myles Wahl
金额：
$ 51.64万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-06 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629069
关键词：
Affect Alleles Animals Autophagocytosis Biological Models Breeding CA-19-9 Antigen Cancer Etiology Cell Compartmentation Cell Line Cell physiology Cessation of life Collaborations Complex Consultations DNA Damage Data Dedications Development Diagnostic Procedure Disease Disease Resistance Drug Combinations Drug resistance Enrollment Ensure Epigenetic Process Epithelium Evaluation Exhibits Fibroblasts Genes Genotype Goals Heterogeneity Histone Deacetylase Human Image Immune Immune system Immunotherapy In Situ Injections Investigational Therapies Isogenic transplantation KPC model Knowledge LIF gene Lead Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Modeling Monitor Mus Mutate Operative Surgical Procedures Organoids Pancreas Pancreatic Ductal Adenocarcinoma Paracrine Communication Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Procedures Protocols documentation Records Refractory Disease Regimen Reproducibility Reproducibility of Results Research Research Project Grants Resistance Role STAT3 gene Services Standardization Techniques Testing Therapeutic Therapeutic Studies Therapeutic Trials Time Transplantation Treatment Efficacy Ultrasonography United States Viral Work chemotherapy cohort cost cost effectiveness design diagnostic strategy drug sensitivity efficacy testing genetic manipulation imaging modality improved in vitro Model in vivo in vivo Model mouse model neoplastic cell novel therapeutic intervention organoid transplantation pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic tumorigenesis pre-clinical programs resistance mechanism response success synergism therapy resistant transmission process treatment response treatment strategy tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis tumorigenic

项目摘要

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.

项目摘要 – 核心 3：鼠标模型核心鼠标模型核心（MM Core）将提供必要的增值服务来支持所有 P01 项目。由于所有项目都提出用小鼠模型进行临床前实验性治疗试验，此类试验将受益于专业的专业人员，统一的程序和标准化的成像协议将能够比较整个 P01 的治疗方案，并确保所有方案的可靠性、可重复性和一致性为了支持这些目标，MM 核心有三个具体目标。提供小鼠和人体材料的原位移植服务，用于鉴定细胞 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耐药性，并测试克服新策略这些挑战历来限制了长期治疗的成功，MM Core 将使用原位治疗。移植目的：1) 确定 HDAC 抑制与 DNA 损伤剂协同作用的能力，重新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 STAT3 在肿瘤微环境中的缺失对肿瘤生长的影响（项目 2），以及 3) 确定肿瘤生长的程度 CA-19-9 水平影响自噬（项目 3）。在 KPC 本地模型中生成足够多的肿瘤，以对最有希望的肿瘤进行生存研究每个研究项目中确定的药物组合方案都具有挑战性，因为小鼠必须这样做。进行繁殖和基因分型，然后必须在适当且可重复的时间招募患有肿瘤的动物使用超声成像来评估肿瘤大小的点 MM Core 将使 KPC 模型能够用于受益于在注册所需的专业诊断技术方面具有专业知识的敬业工作人员的方式具有 5-8 毫米肿瘤的动物，这将确保生存所需饲养的一致性。为了最大限度地减少所需的动物数量和产生的成本，决定采用哪种药物组合。将用于 KPC 生存研究将基于对所有原位移植数据的评估项目负责人与 EAB 协商，药物组合在 KPC 中显示出显着的生存益处。然后将在第二次试验中评估模型，以确保第三个目标的可重复性。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这种独特且要求严格的技术将由核心进行优化，以实现均匀性和一致性。在其他应用中，该程序将在项目 3 中广泛用于描述 AMPK 和 ULK1/2 在肿瘤发生中的作用综合起来，MM Core 将提供可靠、可重复的、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和本土小鼠模型以及超声成像来研究微环境。