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

摘要 动物模型和实验治疗核心（AMETC）的总体目标是为以下方面提供支持： 计划和执行动物实验的项目，开发，维护和提供动物模型 并探索项目中出现的数据、试剂和模型的治疗效用。 胰腺癌的发展是一个逐步的过程，伴随着一系列的组织学和遗传学变化。 这些变化最终导致侵袭性胰腺导管癌（PDAC）。最近，重大进展 在动物模型的开发中，PDAC的发生、发展和转移都有一定的研究价值。基因 工程小鼠模型（GEMM）已经成为研究癌症进展的强大的临床前模型， 确定癌基因和肿瘤抑制因子的作用，肿瘤微环境的作用， 在体内治疗癌症的策略。许多实验室开发的几种GEMM， 癌基因的过度表达或肿瘤抑制因子的破坏，以概括整个谱， 肿瘤前病变和模仿人类PDAC进展和转移的模式。其中，针对 内源性KrasG 12 D等位基因在鼠胰腺祖细胞中的表达作为更好的模型， 胰腺癌，因为发现激活的KrasG 12 D突变是PDAC启动的早期遗传事件， 它的进展。这些小鼠发展成肿瘤前和侵袭性PDA，并与伴随的 p16和Trp 53突变紧密地概括了许多遗传、组织学和病理生理学的变化， 人类疾病的特征。除了KC车型外，动物芯目前还拥有 胰腺癌和囊性病变的其他动物模型包括KPC（突变型Kras和p53）、DPC 4（用于 IPMN）模型。此外，UNMC研究人员拥有基于CRISPR/Cas9的尖端方法来开发 粘蛋白基因的条件性敲除。除了现有的模型，AMETC的主要任务之一是 将开发MUC 16的新模型，这些模型在MUC 16敲除和 转基因动物，并开发具有KC和KPC的复合系，以确定MUC 16在胰腺癌中的作用。 癌症病理学核心小组还将支持研究人员规划和开展研究， 原位移植模型、成像和数据分析。核心将开发新型试剂（新抗体 抗人和鼠MUC 16）、细胞系和来自新产生的动物模型的类器官。此外 发展，维护，表征和供应动物，核心将参与开发新的 试点项目，特别是在MUC 16目标的背景下。MUC 16转基因动物将用于测试 UNMC的一个小组正在开发基于重组MUC 16的纳米颗粒疫苗。芯会 还测试了现有MUC 16抗体作为冷治疗剂或作为递送细胞毒性剂的载体的效用 比如药物毒素或放射性核素总体而言，核心B将支持动物研究的所有方面的项目， 根据具有转化目标的项目的结果进行探索性研究。

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.