Dual Modality System for Imaging Colon Cancer in Mice

小鼠结肠癌模型是确定特定基因在结肠癌中的作用的重要实验工具。 致癌作用，研究肿瘤的发生和发展，并测试潜在的化学预防和 治疗化合物。通常，小鼠研究结果由处死和结肠组织确定。 收获用于诸如肿瘤计数、免疫组织化学和各种测定的程序。因为每种动物 只能分析一次，必须进行统计学上的时间点比较。通过这种方法， 不可能知道病变的进展（和可能的消退）历史。 我们正在改变目前的破坏性范例，通过使用微型组合反射 和荧光内窥镜。我们目前的内窥镜包含光学相干断层扫描和激光 诱导荧光，以实现时间序列的非破坏性、高分辨率和高灵敏度成像 动物个体疾病的可视化。在目前的资助期间，我们进行了几项研究， 证明了双模态成像在可视化疾病进展方面的实用性，有和没有靶向 荧光和散射造影剂。在这次更新中，我们将改进成像仪器， 根据我们的经验和小鼠成像社区的需求，我们将利用 该技术用于致癌作用和化学预防/治疗的科学研究。我们 技术将能够回答有关疾病进展和消退的问题， 很难，如果不是不可能的话，与当前的（牺牲和组织收获）范例。具体目标是： 1.增强反射/荧光内窥镜系统的能力。我们将修改我们的 内窥镜增加色素内窥镜的放大表面视图，以查看最早的假定病变， 异常隐窝病灶（ACF）。其他系统改进包括速度和自动化增强。 2.开发新型靶向造影剂。我们将继续开发靶向造影剂， 主要针对VEGFR和EGFR靶点。金纳米颗粒将用作OCT报告物。LIF 报告物将包括花青染料、无镉纳米点和上转换镧系元素颗粒。 3.进行化学预防和化学治疗研究。我们将进行四项研究：a）如何 ACF和胃肠道肿瘤进展为腺瘤和/或腺癌？B）罐处理 与<$-二氟甲基鸟氨酸（DFMO）和/或舒林酸消退腺瘤和预防腺癌？ c）RAS癌基因在舒林酸预防氧化偶氮甲烷诱导的癌症中发挥什么作用？d）、 舒林酸的替代方案能否以较低剂量提供有效的化学预防？ 在下一个资助期结束时，我们预计将开发出一种功能强大的内窥镜系统 并在化学预防/化学疗法的基础科学方面取得了重大进展， 应用于人类结肠癌的预防和治疗。

Mouse models of colon cancer are a critical experimental tool for determining the role of specific genes in carcinogenesis, studying tumor initiation and progression, and testing potential chemopreventive and therapeutic compounds. Typically, mouse study outcomes are determined by sacrifice and colon tissue harvesting for procedures such as tumor count, immunohistochemistry, and various assays. Since each animal can only be analyzed once, comparison across timepoints must be done statistically. With this method, it is impossible to know the progression (and possible regression) history of a lesion. We are changing the current destructive paradigm through the use of miniaturized combined reflectance and fluorescence endoscopes. Our current endoscopes contain optical coherence tomography and laser induced fluorescence to enable non-destructive, high resolution and high sensitivity imaging for time-serial visualization of an individual animal's disease. In the current funding period, we performed several studies to prove the utility of dual-modality imaging to visualize disease progression, with and without targeted fluorescence and scattering contrast agents. In this renewal, we will refine the imaging instrumentation and contrast agents based on our experience and the needs of the mouse imaging community. We will then utilize this technology for scientifically-compelling studies of carcinogenesis and chemoprevention/therapy. Our technology will enable questions regarding disease progression and regression to be answered that are difficult, if not impossible, to do with the current (sacrifice and tissue harvest) paradigm. The specific aims are: 1. Enhance the capability of the reflectance/fluorescence endoscopic systems. We will modify our endoscope to add a magnifying surface view for chromoendoscopy, to view the earliest putative lesion, aberrant crypt foci (ACF). Other system improvements include speed and automation enhancements. 2. Develop novel targeted contrast agents. We will continue to develop targeted contrast agents, focusing on the targets VEGFR and EGFR. Gold nanoparticles will be used as OCT reporters. LIF reporters will include cyanine dyes, cadmium-free nanodots, and upconverting lanthanide particles. 3. Perform chemoprevention and chemotherapeutic studies. We will perform four studies: a) How do ACF and gastrointestinal neoplasias progress to adenoma and/or adenocarcinoma? b) Can treatment with ¿-difluoromethylornithine (DFMO) and/or sulindac regress adenoma and prevent adenocarcinoma? c) What role does the RAS oncogene play in sulindac prevention of azoxymethane-induced cancer? d) Can an alternative scheduling of sulindac provide effective chemoprevention at a lower dose? At the conclusion of this next funding period, we expect to have developed a powerful endoscopy system and to have made significant advances in the basics science of chemoprevention/chemotherapy, which can be applied to the prevention and treatment of colon cancer in humans.