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

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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.