Mouse models of colon cancer are a critical experimental tool for determining the role of specific genes incarcinogenesis studying tumor initiation and progression and testing potential chemopreventive andtherapeutic compounds. Typically mouse study outcomes are determined by sacrifice and colon tissueharvesting for procedures such as tumor count immunohistochemistry and various assays. Since each animalcan only be analyzed once comparison across timepoints must be done statistically. With this method it isimpossible to know the progression (and possible regression) history of a lesion. We are changing the current destructive paradigm through the use of miniaturized combined reflectanceand fluorescence endoscopes. Our current endoscopes contain optical coherence tomography and laserinduced fluorescence to enable non-destructive high resolution and high sensitivity imaging for time-serialvisualization of an individual animal's disease. In the current funding period we performed several studies toprove the utility of dual-modality imaging to visualize disease progression with and without targetedfluorescence and scattering contrast agents. In this renewal we will refine the imaging instrumentation andcontrast agents based on our experience and the needs of the mouse imaging community. We will then utilizethis technology for scientifically-compelling studies of carcinogenesis and chemoprevention/therapy. Ourtechnology will enable questions regarding disease progression and regression to be answered that aredifficult 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 systemand to have made significant advances in the basics science of chemoprevention/chemotherapy which can beapplied to the prevention and treatment of colon cancer in humans.