A mouse model for p120 downregulation in cancer
癌症 p120 下调的小鼠模型
基本信息
- 批准号:7233250
- 负责人:
- 金额:$ 28.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-08-01 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:A MouseAddressAnimal ModelAnimalsAzoxymethaneBiologicalBreastCadherinsCancer ModelCell-Cell AdhesionColonColon CarcinomaColonic NeoplasmsComplexConditionCultured CellsDataDevelopmentDiseaseDown-RegulationE-CadherinEmbryoEpigenetic ProcessEventFigs - dietaryGastrointestinal tract structureGeneticGenetic ModelsGenus ColaHumanIn VitroInflammatory Bowel DiseasesKnock-outKnockout MiceLeadLiteratureLungMalignant NeoplasmsMammary glandMediatingModelingMolecularMusMutationNeoplasm MetastasisPathologyPhenocopyPhenotypeProstatePsoriasisRoleSkinSmall Interfering RNASpecificityStudy modelsSyndromeTestingTimeTissuesTransgenesTransgenic MiceWild Type MouseWorkadenomabasechemical carcinogenclinically relevantgastrointestinalin vivointerestintestinal epitheliummouse modelnovelnovel strategiesresearch studytumortumor progressionvillin
项目摘要
DESCRIPTION (provided by applicant): E-cadherin downregulation in cancer occurs frequently and is clearly a pivotal event in the transition to metastasis. Interestingly, recent studies of nearly all of the major human tumor types also reveal frequent downregulation of p120, but the mechanism and consequences of p120 downregulation are unknown. Moreover, p120 downregulation in tumors has been largely ignored because until recently there was no compelling reason to focus on the issue. This proposal is based primarily on three key observations, two of which are included as preliminary data. First, p120 is required for E-cadherin stability. Second, p120 expression is frequently downregulated or regionally absent in a significant subset of the most common human cancers (eg, colon, prostate, lung, breast, and others). Third, DN-cadherins strongly promote tumor progression and/or metastasis in animal models, and probably act via sequestering p120. The data provides compelling evidence that p120 downregulation might contribute to E-cadherin downregulation in a subset of human tumors. We have constructed a conditional p120 knockout (KO) mouse (conventional p120-KO is embryonic lethal), providing the first opportunity to examine p120 function in vivo, and the consequence(s) of p120 downregulation in disease and/or cancer. The mouse intestinal epithelium is an excellent model for studying normal p120 function, and the Min (APC mutation) and Azoxymethane (AOM) mouse models for colon cancer are ideally suited for studying p120 downregulation in cancer. However, disease and tumor modifiers also can have distinct tissue specificities that are essentially unpredictable. To address these issues, (1) We will determine the consequences or p120-loss under otherwise normal conditions using a villin-CreER transgene to control the timing and extent of p120 KO in the gastrointestinal (Gl)-tract. (2) We will directly identify the consequences of p120 downregulation in colon cancer by targeting p120-loss to the Gl-tract in the context of Min and AOM mouse cancer models. (3) We will generate a stochastic p120-deleter mouse model to induce accelerated LOH and address at the whole animal level the hypothesis that p120 is a critical disease and/or tumor modifier in susceptible tissues. Together, these experiments directly address the consequences of p120 downregulation in disease and cancer, and may lead to increased understanding of events mediating the transition to metastasis.
描述(由申请人提供):癌症中E-钙粘蛋白下调频繁发生,并且显然是向转移转变的关键事件。有趣的是,最近对几乎所有主要人类肿瘤类型的研究也揭示了p120的频繁下调,但p120下调的机制和后果尚不清楚。此外,肿瘤中的p120下调在很大程度上被忽视了,因为直到最近才有令人信服的理由关注这个问题。这一建议主要基于三项关键意见,其中两项作为初步数据列入。首先,p120是E-钙粘蛋白稳定性所必需的。第二,p120表达在最常见的人类癌症(例如结肠癌、前列腺癌、肺癌、乳腺癌等)的重要亚组中经常下调或区域性缺失。第三,DN-钙粘蛋白在动物模型中强烈促进肿瘤进展和/或转移,并且可能通过隔离p120起作用。这些数据提供了令人信服的证据表明,p120下调可能有助于在人类肿瘤的一个子集的E-钙粘蛋白下调。我们已经构建了一个条件性p120基因敲除(KO)小鼠(传统的p120-KO是胚胎致死),提供了第一次机会,以检查p120在体内的功能,和疾病和/或癌症的p120下调的后果。小鼠肠上皮是研究正常p120功能的极好模型,Min(APC突变)和Azoxymethane(AOM)结肠癌小鼠模型非常适合研究癌症中p120下调。 然而,疾病和肿瘤修饰物也可以具有本质上不可预测的不同组织特异性。为了解决这些问题,(1)我们将使用villin-CreER转基因来控制胃肠道(GI)中p120 KO的时间和程度,以确定在其他正常条件下p120丢失的后果。(2)我们将通过在Min和AOM小鼠癌症模型中靶向胃肠道p120丢失,直接确定结肠癌中p120下调的后果。(3)我们将建立一个随机的p120缺失小鼠模型来诱导加速的洛缺失,并在整个动物水平上阐明p120是易感组织中的一种严重疾病和/或肿瘤修饰因子的假设。总之,这些实验直接解决了疾病和癌症中p120下调的后果,并可能导致对介导转移的事件的理解增加。
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)
专利数量(0)
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ALBERT B REYNOLDS的其他文献
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{{ truncateString('ALBERT B REYNOLDS', 18)}}的其他基金
Role of p120-catenin in cell transformation
p120-连环蛋白在细胞转化中的作用
- 批准号:
8724525 - 财政年份:2013
- 资助金额:
$ 28.73万 - 项目类别:
Role of p120-catenin in cell transformation
p120-连环蛋白在细胞转化中的作用
- 批准号:
8579736 - 财政年份:2013
- 资助金额:
$ 28.73万 - 项目类别:
A mouse model for p120 downregulation in cancer
癌症 p120 下调的小鼠模型
- 批准号:
7913602 - 财政年份:2009
- 资助金额:
$ 28.73万 - 项目类别:
A mouse model for p120 downregulation in cancer
癌症 p120 下调的小鼠模型
- 批准号:
6969685 - 财政年份:2005
- 资助金额:
$ 28.73万 - 项目类别:
A mouse model for p120 downregulation in cancer
癌症 p120 下调的小鼠模型
- 批准号:
7103601 - 财政年份:2005
- 资助金额:
$ 28.73万 - 项目类别:
A mouse model for p120 downregulation in cancer
癌症 p120 下调的小鼠模型
- 批准号:
7619037 - 财政年份:2005
- 资助金额:
$ 28.73万 - 项目类别:
Mechanism of p120 downregulation in human cancer
人类癌症中 p120 下调的机制
- 批准号:
6856420 - 财政年份:2005
- 资助金额:
$ 28.73万 - 项目类别:
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