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Core 2: Animal Model and Experimental Therapeutics Core [AMETC]

核心 2：动物模型和实验治疗核心 [AMETC]

基本信息

批准号：
10203866
负责人：
MANEESH JAIN
金额：
$ 25.32万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-08 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203866
关键词：
Alleles Animal Experiments Animal Model Animals Antibodies Biological Biological Markers Biopsy CA-125 Antigen CRISPR/Cas technology Cachexia Cell Line Cell-Cell Adhesion Chemosensitization Cold Therapy Collection Cyst Fluid Cystic Lesion Cytotoxic agent Data Data Analyses Development Diagnosis Disease Doctor of Philosophy Drug resistance Duct (organ) structure Epithelial Euthanasia Event Generations Genes Genetic Genetically Engineered Mouse Goals Grouping Growth Factor Receptors Histologic Histopathology Human Human Characteristics Image Investigational Therapies KRASG12D Knockout Mice Knowledge Laboratories Lead Lesion Liquid substance MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Measurement Membrane Modeling Monoclonal Antibodies Mucins Mus Mutation Neoplasm Metastasis Oncogenes Operative Surgical Procedures Organ Harvestings Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Carcinoma Pancreatic Intraepithelial Neoplasia Pattern Peritoneal Fluid Pharmaceutical Preparations Pilot Projects Plasma Play Pre-Clinical Model Procedures Prognosis Protocols documentation Radioisotopes Reagent Receptor Signaling Recombinants Research Research Personnel Residual Neoplasm Role Series Services Statistical Data Interpretation Stromal Cells Surface TP53 gene Testing Therapeutic Toxin Training Transgenic Animals Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Tumor Volume Vaccines base biomarker discovery cancer cell cancer therapy clinically relevant conditional knockout cost effective design human disease in vivo islet stem cells knockout animal member mouse model mutant nanoparticle neoplastic novel novel therapeutic intervention overexpression pancreatic cancer model programs research and development targeted treatment transplant model treatment planning treatment strategy tumor tumor microenvironment tumor progression

项目摘要

ABSTRACT The overall goal of Animal Models and Experimental Therapeutics Core (AMETC) is to provide support to projects for planning and executing animal experiments, develop, maintain and supply animal models to projects as needed and explore the therapeutic utility of data, reagents and models that emerge from the projects. Pancreatic cancer develops in a step-wise progression, accompanied by series of histologic and genetic changes, which ultimately lead to invasive pancreatic ductal carcinoma (PDAC). Recently, major progress has been made in the development of animal as models of PDAC initiation, progression and metastasis. Genetically engineered mouse models (GEMMs) have emerged as powerful preclinical models to study cancer progression, define the role of oncogenes and tumor suppressors, role of tumor microenvironment and evaluate therapeutic strategies for the treatment of cancer in vivo. Several GEMMs developed by many laboratories involving overexpression of oncogenes or disruption of tumor suppressors to recapitulate the entire spectrum of preneoplastic lesions and mimic the patterns of human PDAC progression and metastasis. Of these, targeted expression of an endogenous KrasG12D allele in murine pancreatic progenitor cells serve as a better model for pancreatic cancer because activated KrasG12D mutations found to be early genetic events in PDAC initiation and its progression. Such mice developed both preneoplastic and invasive PDA, and cooperated with a concomitant p16 and Trp53 mutations that to closely recapitulate many of the genetic, histological and pathophysiological characteristics of the human disease. In addition to the KC model, the animal core is currently in possession other animal models for pancreatic cancer and cystic lesion including KPC (mutant Kras and p53), DPC4 (for IPMN) models. Further, UNMC investigators have cutting edge CRISPR/Cas9 based approaches to develop conditional knockout of mucin genes. In addition to the existing models, one of the major tasks of the AMETC will be to develop novel models for MUC16 that are proposed in the projects including MUC16 knockout and transgenic animals and develop compound lines with KC and KPC to define the role of MUC16 in pancreatic cancer pathobiology. The Core will also support investigators for planning and undertaking studies involving orthotopic transplant models, imaging and data analysis. The core will develop novel reagents (new antibodies against human and murine MUC16), cell lines and organoids from newly generated animal models. In addition to developing, maintaining, characterizing and supplying animals, the core will be involved in developing new pilot projects particularly in the context of MUC16-targeting. The MUC16 transgenic animals will be used to test recombinant MUC16-based nanoparticle vaccine that is being developed by a group at UNMC. The core will also test the utility of existing MUC16 antibodies as cold-therapeutics or as vehicles to deliver cytotoxic agents like drugs, toxins or radionuclides. Overall, Core B will support the projects in all aspects of animal studies and undertake exploratory studies based of the findings of the projects with a translational objective.

摘要