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 计划和执行动物实验的项目，开发、维护和向项目提供动物模型 根据需要，探索项目中出现的数据、试剂和模型的治疗效用。 胰腺癌是一种循序渐进的发展过程，伴随着一系列的组织学和遗传学 改变，最终导致侵袭性胰腺导管癌(PDAC)。最近，取得了重大进展 在动物发育过程中作为PDAC发生、发展和转移的模型。从基因上讲 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， 明确癌基因和抑癌基因的作用、肿瘤微环境的作用和评价治疗 体内治疗癌症的策略。由多个实验室开发的几种GEMM，涉及 癌基因的过度表达或肿瘤抑制基因的中断，以概括整个谱 癌前病变，并模仿人类PDAC的进展和转移模式。其中，有针对性的 内源性KrasG12D等位基因在小鼠胰腺前体细胞中的表达可作为更好的模型 胰腺癌是因为激活的KrasG12D突变被发现是PDAC启动和早期遗传事件 它的进程。这样的小鼠发生了癌前病变和侵袭性PDA，并与伴随的 P16和Trp53突变，紧密概括了许多遗传学、组织学和病理生理学 人类疾病的特点。除了KC模型外，动物核心目前还拥有 其他胰腺癌和囊性病变的动物模型包括KPC(突变的Kras和P53)、DPC4(用于 IPMN)模型。此外，赔偿委员会调查员拥有基于CRISPR/CAS9的尖端方法来制定 有条件地敲除粘蛋白基因。除了现有的型号外，AMETC的主要任务之一 将为MUC16开发新的模型，这些模型在包括MUC16基因敲除和 转基因动物并建立KC和KPC复合系以确定MUC16在胰腺中的作用 癌症病理生物学。核心还将支持调查人员规划和开展涉及以下方面的研究 原位移植模型、影像及数据分析。核心将开发新的试剂(新的抗体 抗人和小鼠MUC16)、细胞系和来自新产生的动物模型的有机化合物。此外 对于开发、维护、表征和供应动物，核心将涉及到开发新的 试点项目，特别是针对MUC16的试点项目。MUC16转基因动物将用于测试 UNMC的一个小组正在开发基于MUC16的重组纳米颗粒疫苗。核心将会 还要测试现有的MUC16抗体作为冷疗药物或作为输送细胞毒剂的载体的效用 比如毒品、毒素或放射性核素。总体而言，核心B将支持动物研究和研究的所有方面的项目 根据项目的结果进行探索性研究，目标是翻译。

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.