Although the increased risk of colorectal cancer among patients with ulcerative colitis is well documented, little attention has been given to the development of a chemopreventive regimen for this high- risk population. Based on this deficiency, a critical need exists to identify molecular targets for early intervention and develop efficacious regimens for the chemoprevention of colitis-associated neoplasia. Because results from several prior studies by this group provide strong evidence that the two morphological subtypes of colitis-associated colorectal neoplasias (flat and polypoid) arise via different geneti pathways, effective chemoprevention will only be realized once an in-depth understanding of the molecular mechanisms that contribute to the formation of each lesion subtype has been achieved. The hypothesis of the proposed experimentation is that morphological subtypes of colitis-associated colorectal dysplasias arise from either ß-catenin-mediated enhanced proliferation (polypoid lesions) or deficiencies in p53-dependent apoptotic signaling (flat lesions. Rationale for this hypothesis is provided by preliminary analyses in the dextran sulfate sodium (DSS) model of induced colitis that indicate that loss of p53 function and decreased expression of downstream target genes are prevalent in flat lesions, while ß-catenin mutations and nuclear localization of ß-catenin predominate in polypoid lesions bearing wild-type p53. A series of mechanistic studies are proposed to define the "molecular switch" that regulates the formation of flat vs. polypoid lesions and assess the feasibility of disrupting p53 and ß-catenin signaling s a strategy for the prevention of colitis-associated colorectal cancer. The ability of mutant ß-catenin or loss of function of p53 to drive the formation of polypoid and flat dysplasias, respectively, will be evaluated in Aim 1 in genetically defined mice with DSS-induced colitis. The molecular mechanisms underlying the propensity to develop each subtype of lesion will be investigated in parallel in cultured human colon carcinoma cells with defined mutations in ß-catenin or p53 by examining p53 expression and activation, subcellular localization of ß-catenin and the expression of mediators of p53 activity (Siah-1, Mdm2/X and miR-34). In Aim 2, the chemopreventive activity afforded against colitis-associated neoplasia by administering agents that reactivate p53 (CP31398) or inhibit ß-catenin-mediated TCF signaling (ICG-001) will be determined in wild-type Tcf4 luciferase reporter mice. Translation of these murine data to a clinical setting will be initiated with an analysis of the proliferative vs. apoptotic capacity of human flat and polypoid colitis-associated dysplasias and complemented by RNA expression profiling of each lesion subtype (Aim 3). The resulting data are anticipated to provide novel insight into the genetic basis of flat and polypoid colitis-associated dysplasias and inform the rational design of chemopreventive regimens for early intervention in the development of colitis-associated lesions, in particular flat dysplasias that often escape detection.