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:
- 金额:$ 40.83万
- 依托单位:
- 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:
- 关键词:AnimalsApoptosisApoptoticAttentionBAX geneCASP3 geneCaspaseCell LineCell ProliferationChemopreventionChemopreventive AgentClinicalCoculture TechniquesColitisColonColon CarcinomaColorectalColorectal CancerColorectal NeoplasmsComplementDataDetectionDevelopmentDiseaseDysplasiaEarly DiagnosisEarly InterventionEndoscopyExhibitsFaceGene TargetingGeneral PopulationGenesGeneticGenetic EngineeringGenetic TranscriptionGoalsGrowthHealthHumanImageIncidenceInflammationInflammatory Bowel DiseasesLasersLeadLesionLoss of HeterozygosityLuciferasesMalignant Epithelial CellMalignant NeoplasmsMeasuresMediatingMediator of activation proteinModelingMolecularMolecular ProfilingMolecular TargetMusMutationNeoplasmsNuclearPathway interactionsPatientsPhosphorylationPolypoid LesionPopulationPost-Translational Protein ProcessingPrevention strategyPreventiveProteinsRegimenReporterRiskSOX17 geneSeriesSignal TransductionSodium Dextran SulfateSystemTP53 geneTechnologyTestingTissuesTranslationsTumor Necrosis Factor Ligand Superfamily Member 6Ulcerative Colitisbasebeta catenincancer riskclinically relevantcolon dysplasiadesigndifferential expressionhigh riskinsightloss of functionmacrophagemouse modelmutantmutational statusnoveloverexpressionprotein expressionresearch studytargeted treatmenttumor
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(由适用提供):尽管溃疡性结肠炎患者的结直肠癌风险增加了,但对这种高危人群的化学预防治疗方案的发展很少。基于这种缺乏,存在着重要的需求,以确定早期干预和发展的分子靶标
与结肠炎相关的肿瘤化学预防的有效方案。由于该小组的几项先前研究的结果提供了有力的证据,表明与结肠炎相关的结直肠瘤(Flat and Polypoid)的两种形态亚型通过不同的Geneti途径产生,因此只有在对分子机制的深入了解有助于每种Lesion subtype的形成中,才能实现有效的化学预防。提出的实验的假设是,结肠炎相关的结直肠发育不全的形态亚型是由β-catenin介导的增强(息肉性病变)的增强(息肉性病变)或p53依赖性质子性信号传导的增殖(息肉性病变)或缺乏症(p53依赖性的固定病变)。 (DSS)诱导结肠炎的模型表明,p53功能的丧失和下游靶基因的表达在平坦的病变中普遍存在,而β-catenin突变和β-catenin的核定位占多体性病变中的β-catenin占主导地位p53。 p53和β-catenin信号的病变和评估是预防与结肠炎相关的结直肠癌的策略。将在培养的人类结肠癌细胞中并行研究,在-catenin或p53中定义的突变,通过检查p53表达和激活,β-catenin的亚细胞定位以及p53活性的中介体的表达(sia-siah-1,MIR M.D.2,在β-蛋白蛋白或p53中定义突变),将在培养的人类结肠癌细胞中并行研究,并在培养的人类结肠癌细胞中并行研究P53活性(sia-1 Aia-1 AiA 2 Aia23/siMIR)。在AIM 2中,通过给p53(CP31398)或抑制β-catenin介导的TCF信号传导(ICG-001)的药物通过给予结肠炎相关的肿瘤的化学预防活性,将在野生型TCF4 Luciferase Reporase Reporter小鼠中确定。这些鼠数据将这些鼠数据转换为临床环境,将通过分析人类扁平和息肉性结肠炎相关的发育异常的增殖与凋亡能力的分析,并通过每个病变亚型的RNA表达分析完成(AIM 3)。预计所得数据将提供对扁平和多杂体性结肠炎相关的发育不全的遗传基础的新洞察力,并为化学预防方案的合理设计提供了用于早期干预结肠炎相关病变的早期干预,特别是经常逃脱检测的平坦发育不良。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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MARGIE L. CLAPPER其他文献
MARGIE L. CLAPPER的其他文献
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