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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.

项目总结-核心3：鼠标模型核心