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关键实验工具 癌症发生，研究肿瘤的发生和发展，并测试潜在的化学预防和 治疗性化合物。通常，小鼠的研究结果由牺牲和结肠组织决定。 采集用于肿瘤计数、免疫组织化学和各种检测的程序。因为每只动物 只能分析一次，跨时间点的比较必须以统计方式进行。使用这种方法，它是 不可能知道病变的进展(和可能的退化)历史。 我们正在通过使用微型化的组合反射率来改变目前的破坏性范例 还有荧光内窥镜。我们目前的内窥镜包括光学相干断层扫描和激光 诱导荧光技术实现时间序列的无损、高分辨率和高灵敏度成像 对单个动物疾病的可视化。在目前的资助期间，我们进行了几项研究，以 证明在有针对性和无针对性的情况下，双模式成像在可视化疾病进展方面的效用 荧光和散射造影剂。在这次更新中，我们将改进成像仪器和 造影剂基于我们的经验和鼠标成像界的需求。然后我们将利用 这项技术为癌症发生和化学预防/治疗提供了科学上令人信服的研究。我们的 技术将使关于疾病进展和回归的问题能够得到回答，这些问题是 很难，如果不是不可能的话，与当前的(牺牲和组织采集)范例相适应。具体目标是： 1.增强反射/荧光内窥镜系统的性能。我们将修改我们的 内窥镜以增加用于染色内窥镜的放大表面视图，以查看最早的推定病变， 异常隐窝病灶(ACF)。其他系统改进包括速度和自动化增强。 2.研制新型靶向造影剂。我们将继续开发靶向造影剂， 聚焦于VEGFR和EGFR的目标。金纳米颗粒将被用作OCT记者。寿命 记者将包括菁染料、无镉纳米点和上转换稀土粒子。 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)可以接受治疗 使用二氟甲基鸟氨酸(DFMO)和/或舒林酸可以消退腺瘤和预防腺癌？ C)ras癌基因在舒林酸预防偶氮甲烷诱导的癌症中起什么作用？d) 舒林酸的替代方案能否以较低的剂量提供有效的化学预防？ 在下一个资助期结束时，我们希望开发出一种强大的内窥镜系统 并在化学预防/化疗的基础科学方面取得重大进展，这可以是 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.