Targeted Chemoprevention of Flat and Polypoid Colitis-associated Dysplasias

扁平和息肉样结肠炎相关不典型增生的靶向化学预防

基本信息

批准号：
9130172
负责人：
MARGIE L. CLAPPER
金额：
$ 40.83万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130172
关键词：
Animals Apoptosis Apoptotic Attention BAX gene CASP3 gene Caspase Cell Line Cell Proliferation Chemoprevention Chemopreventive Agent Clinical Coculture Techniques Colitis Colon Colon Carcinoma Colorectal Colorectal Cancer Colorectal Neoplasms Complement Data Detection Development Disease Dysplasia Early Diagnosis Early Intervention Endoscopy Exhibits Face Gene Targeting General Population Genes Genetic Genetic Engineering Genetic Transcription Goals Growth Health Human Image Incidence Inflammation Inflammatory Bowel Diseases Lasers Lead Lesion Loss of Heterozygosity Luciferases Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Mediator of activation protein Modeling Molecular Molecular Profiling Molecular Target Mus Mutation Neoplasms Nuclear Pathway interactions Patients Phosphorylation Polypoid Lesion Population Post-Translational Protein Processing Prevention strategy Preventive Proteins Regimen Reporter Risk SOX17 gene Series Signal Transduction Sodium Dextran Sulfate System TP53 gene Technology Testing Tissues Translations Tumor Necrosis Factor Ligand Superfamily Member 6 Ulcerative Colitis base beta catenin cancer risk clinically relevant colon dysplasia design differential expression high risk insight loss of function macrophage mouse model mutant mutational status novel overexpression protein expression research study targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：虽然溃疡性结肠炎患者患结直肠癌的风险增加已有充分记录，但针对这一高危人群开发化学预防方案却很少受到关注，因为这一缺陷迫切需要。存在的目的是确定早期干预的分子目标并开发结肠炎相关肿瘤的有效化学预防方案因为该小组先前的几项研究结果提供了强有力的证据，表明结肠炎相关结直肠肿瘤的两种形态亚型（扁平型和息肉型）通过不同的遗传途径产生，因此有效的化学预防只能是有效的。一旦实现了对每种病变亚型形成的分子机制的深入了解，所提出的实验的假设是形态学亚型。结肠炎相关的结直肠发育不良是由 β-连环蛋白介导的增殖增强（息肉样病变）或 p53 依赖性细胞凋亡信号传导缺陷（平坦病变）引起的。这一假设的基本原理是通过右旋糖酐硫酸钠 (DSS) 模型的初步分析提供的。诱导结肠炎，表明扁平病变中普遍存在 p53 功能丧失和下游靶基因表达减少，而 ß-catenin 突变和核定位β-连环蛋白在携带野生型 p53 的息肉样病变中占主导地位，提出了一系列机制研究来定义调节扁平与息肉样病变形成的“分子开关”，并评估破坏 p53 和 ß-连环蛋白信号传导的可行性。预防结肠炎相关结直肠癌的策略 β-连环蛋白突变或 p53 功能丧失驱动息肉状和扁平状形成的能力。目标 1 将在患有 DSS 诱导的结肠炎的基因定义小鼠中分别评估发育不良的分子机制，并将在具有 β-连环蛋白确定突变的培养的人结肠癌细胞中并行研究形成每种病变亚型的倾向的分子机制。或 p53，通过检查 p53 表达和激活、β-连环蛋白的亚细胞定位以及 p53 活性介质（Siah-1、Mdm2/X 和在目标 2 中，通过施用重新激活 p53 (CP31398) 或抑制 ß-catenin 介导的 TCF 信号传导 (ICG-001) 的药物来对抗结肠炎相关肿瘤的化学预防活性将在野生型 Tcf4 荧光素酶中测定。将通过分析人类平板的增殖与凋亡能力来启动这些小鼠数据的临床应用。和息肉样结肠炎相关的不典型增生，并辅以每种病变亚型的 RNA 表达谱（目标 3）。预计所得数据将为平坦和息肉样结肠炎相关的不典型增生的遗传基础提供新的见解，并为化学预防方案的合理设计提供信息。用于早期干预结肠炎相关病变的发展，特别是经常逃避检测的扁平发育不良。