(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation
(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化
基本信息
- 批准号:9101320
- 负责人:
- 金额:$ 35.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-09 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenomatous Polyposis ColiAllelesAutomobile DrivingAzoxymethaneBindingCancer EtiologyCarcinogensCell NucleusCellsCessation of lifeChemopreventionChromosomal StabilityChronicColorectalColorectal CancerColorectal NeoplasmsConstipationCreativenessDataDevelopmentDiseaseEpithelialEpithelial CellsEpitheliumEventFeedbackFunctional disorderFutureGeneticGenetic TranscriptionHereditary DiseaseHomeostasisHormone replacement therapyHormonesInduced MutationIntestinesKnowledgeLigandsLinkMalignant NeoplasmsMediatingMetabolicMolecularMusMutationNuclearOralOutcomePatientsPremalignantPropertyRectumRegulationRoleSignal TransductionSupplementationTestingTransgenic OrganismsTranslatingTranslationsadenomabasebeta catenincancer chemopreventioncolorectal cancer preventiondesignguanylinhormone deficiencyinnovationinsightmouse modelmutantmutant mouse modelnoveloriginalityparacrinepeptide hormonepreventprogramspublic health relevancereceptorreconstitutiontumortumor initiationtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Colorectal cancer is the 4th most common cancer and 2nd leading cause of cancer death. In >90% of sporadic cases, colorectal cancer initiates as mutations in APC (~85%) or its downstream degradation target, β-catenin (~5%). These mutations result in accumulation of β-catenin which translocates to the nucleus and regulates transcription driving epithelial dysfunction and formation of the premalignant field (adenomas). While a role for APC and β-catenin mutations in transformation is established, gaps in knowledge reflect an incomplete understanding of the pathophysiological events linking these mutations to formation of the premalignant field, the mechanisms mediating those events, and their reversibility as a basis for cancer chemoprevention. In that context, guanylin is a paracrine
peptide hormone produced by epithelial cells in the colo-rectum. Guanylin binds to GUCY2C, a receptor which maintains epithelial homeostasis by regulating proliferation, chromosomal stability, and metabolic programming, in part, by preventing β-catenin accumulation. Recently, we revealed that guanylin loss silencing GUCY2C occurs in all colorectal tumors. Further, guanylin is lost in all adenomas, and in premalignant epithelia that precede adenoma formation. Unexpectedly, transgenic expression of guanylin (cannot be lost) in mice eliminated transformation induced by the carcinogen azoxymethane (AOM) which produces β-catenin mutations. Based on these observations, we propose testing the novel hypothesis that that there is a reciprocal feedback loop in which nuclear signaling by mutant APC-β-catenin induces guanylin loss required for transformation because guanylin-GUCY2C blocks β-catenin accumulation necessary for tumorigenesis. Here, the Pathophysiological Aim will test the hypothesis that guanylin loss silencing GUCY2C is required to form the premalignant field produced by mutant APC-β-catenin. These studies will demonstrate that eliminating guanylin in intestinal cells recapitulates the pathophysiology of transformation (guanylin loss mediates the disease). The Mechanistic Aim will test the hypothesis that mutant APC-β-catenin suppresses guanylin transcription because guanylin-GUCY2C blocks β-catenin accumulation required for transformation (this molecular mechanism mediates guanylin loss). These studies will shift the paradigm in colorectal cancer from a genetic disease of irreversible APC-β-catenin mutations to a disease of reversible guanylin insufficiency. The Chemoprevention Aim will test the hypothesis that transgenic guanylin replacement blocks β-catenin accumulation, epithelial dysfunction, and transformation induced by APC-β-catenin mutations (blocking guanylin loss prevents the disease). These studies will establish the chemoprevention paradigm that guanylin replacement eliminates intestinal transformation. In turn, these novel mechanistic insights will provide new opportunities for colorectal cancer prevention, including oral GUCY2C ligand supplementation. The potential for immediate translation is underscored by the approval of the oral GUCY2C ligand, linaclotide, to treat chronic constipation.
简介(申请人提供):结直肠癌是第四大常见癌症,也是癌症死亡的第二大原因。在90%的散发性病例中,结直肠癌以APC(~85%)或其下游降解靶点β-连环蛋白(~5%)突变开始。这些突变导致β-连环蛋白的积聚,该连环蛋白移位到细胞核并调节转录,驱动上皮功能障碍和形成癌前视野(腺瘤)。虽然APC和β-连环蛋白突变在转化中的作用已经确立,但知识的空白反映了对将这些突变与癌前视野的形成联系起来的病理生理事件、介导这些事件的机制以及它们作为癌症化学预防基础的可逆性的不完全理解。在这种情况下,鸟巢是一种旁分泌
结肠直肠上皮细胞产生的多肽激素。鸟苷素与GUCy2C结合,GUCy2C是一种受体,通过调节增殖、染色体稳定性和代谢编程来维持上皮细胞的动态平衡,部分是通过防止β-连环蛋白的积累。最近,我们发现鸟苷素缺失沉默GUCY2C在所有的结直肠肿瘤中都存在。此外,鸟苷素在所有腺瘤以及在腺瘤形成之前的癌前上皮中都缺失。出乎意料的是,鸟苷素(不能丢失)在小鼠中的转基因表达消除了致癌物质偶氮甲烷诱导的转化,这种转化会产生β-连环蛋白突变。基于这些观察,我们建议检验一个新的假设,即存在一个相互反馈环,其中突变的APC-β-连环蛋白的核信号导致转化所需的鸟苷丢失,因为鸟苷-GUC2C阻止了肿瘤发生所需的β-连环蛋白的积累。在这里,病理生理学目的将检验这样的假设,即鸟苷素缺失沉默GUCY2C是形成由突变的APC-β-连环蛋白产生的癌前视野所必需的。这些研究将证明,清除肠道细胞中的鸟苷素重述了转化的病理生理学(鸟苷素丢失介导了疾病)。该机制的目的是验证这样的假设,即突变体Apc-β-catenin抑制鸟苷转录,因为鸟苷-GUC2C阻止了转化所需的β-连环蛋白的积累(这一分子机制介导了鸟苷的丢失)。这些研究将把结直肠癌的研究范式从一种不可逆的apc-β-catenin突变的遗传病转变为一种可逆性鸟苷缺乏的疾病。化学预防的目的是验证这样一种假设,即转基因鸟苷替代阻止β-连环蛋白积累、上皮功能障碍和由APC-β-连环蛋白突变诱导的转化(阻断鸟苷丢失可预防疾病)。这些研究将建立化学预防范式,即鸟苷素替代消除肠道转化。反过来,这些新的机制洞察力将为结直肠癌预防提供新的机会,包括口服GUCY2C配体补充。口服GUCY2C配体linaclotie被批准用于治疗慢性便秘,突显了立即翻译的潜力。
项目成果
期刊论文数量(0)
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SCOTT A WALDMAN其他文献
SCOTT A WALDMAN的其他文献
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{{ truncateString('SCOTT A WALDMAN', 18)}}的其他基金
Neuroprotection by the GUCY2C gut-brain axis in Parkinson's disease
GUCY2C 肠脑轴对帕金森病的神经保护作用
- 批准号:
10740951 - 财政年份:2023
- 资助金额:
$ 35.69万 - 项目类别:
Guanylin GUCY2C axis in Colorectal Cancer Initiation
鸟苷素 GUCY2C 轴在结直肠癌发生中的作用
- 批准号:
9237630 - 财政年份:2017
- 资助金额:
$ 35.69万 - 项目类别:
(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation
(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化
- 批准号:
9922880 - 财政年份:2016
- 资助金额:
$ 35.69万 - 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
- 批准号:
8680189 - 财政年份:2012
- 资助金额:
$ 35.69万 - 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
- 批准号:
8517056 - 财政年份:2012
- 资助金额:
$ 35.69万 - 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
- 批准号:
8895861 - 财政年份:2012
- 资助金额:
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Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
- 批准号:
7828432 - 财政年份:2009
- 资助金额:
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Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
- 批准号:
7941015 - 财政年份:2009
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$ 35.69万 - 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
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6772420 - 财政年份:2003
- 资助金额:
$ 35.69万 - 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
- 批准号:
6685481 - 财政年份:2003
- 资助金额:
$ 35.69万 - 项目类别:
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