Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
基本信息
- 批准号:10217057
- 负责人:
- 金额:$ 65.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:APC geneAPC mutationAPC2 geneAntibodiesApoptosisAttenuatedBindingBiochemistryCancer EtiologyCancer ModelCell MaintenanceCell ProliferationCellsCessation of lifeClathrinClinicalColorectalColorectal CancerComplexCritical PathwaysDevelopmentDrosophila genusEndocytosisGenesGeneticGenetic EngineeringGoalsGrowthHumanHuman EngineeringIn VitroIntestinesKnowledgeLDL-Receptor Related Protein 1LeftLigandsMAP Kinase GeneMaintenanceMalignant NeoplasmsMediatingModelingMolecularMolecular WeightMusMutationNeoplasm MetastasisOrganoidsPathway interactionsPhysiologicalProteinsProteolysisProteomicsPublishingReceptor ActivationRoleScreening procedureSeriesSignal TransductionSignal Transduction PathwaySucroseTP53 geneTestingTherapeuticTranscription CoactivatorTranscriptional ActivationTransforming Growth Factor betaTranslatingTumor Suppressor ProteinsTumorigenicityUnited StatesWNT Signaling PathwayXenograft procedurebasebeta catenincancer cellcell typecolon cancer patientscolon carcinogenesiscolorectal cancer treatmentcost effectivedensitydriver mutationdruggable targetefficacy testingenhancer-binding protein AP-2in vivoinhibitor/antagonistlipoprotein receptor-related protein 6multidisciplinarymutantnovelnovel strategiesnovel therapeutic interventionparalogous genepatient derived xenograft modelpreventreceptorstem cellstumortumor progression
项目摘要
Project Summary
Inhibition of Wnt Receptor Activation by the Tumor Suppressor Adenomatous Polyposis Coli
The long-term objective of this study is to investigate how the tumor suppressor Adenomatous
polyposis coli (APC) inhibits the Wnt signal transduction pathway by regulating the Wnt receptor
complex (signalosome) and to demonstrate how this can be exploited to target APC mutant colorectal
cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance, whereas aberrant
activation of this pathway, which occurs most frequently through mutational inactivation of APC, triggers
the development of the vast majority of CRCs. In the classical model for Wnt signaling, the sole role of
APC is to destabilize the key transcriptional activator in the Wnt pathway, beta-catenin. However, our
recently published findings reveal an additional and entirely new function – APC prevents the
internalization and consequent activation of the signalosome, a novel role that is evolutionarily
conserved. We have shown that: 1) inducible loss of APC is rapidly followed by ligand-independent
signalosome activation; 2) depletion or antibody-mediated inhibition of LRP6 (a signalosome
component) inhibits the stabilization of beta-catenin, the transcriptional activation of Wnt target genes,
and the proliferation of APC mutant cells; and 3) in APC mutant cells, endocytosis of Wnt receptors is
required for the aberrant activation of Wnt signaling. The goal of this project is to use in vitro, ex vivo,
and in vivo approaches to gain a better understanding of how APC inhibits signalosome activation
under physiological conditions and to determine how aberrant activation of the signalosome underlies
the consequences of APC inactivation in tumors. The three specific aims are to: 1) elucidate the
mechanism by which APC loss promotes signalosome assembly in CRC cells; 2) identify the APC
mutant CRC cells most susceptible to LRP6 inactivation; and 3) test the efficacy of LRP6 inactivation
on CRC tumorigenicity in vivo. Because the molecular mechanisms by which APC prevents the
aberrant activation of Wnt signaling are important for our understanding of colorectal carcinogenesis,
the knowledge gained from this study will aid in the development of new therapeutic strategies for the
treatment of CRC and other Wnt-driven cancers.
项目概要
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体激活的抑制
本研究的长期目标是研究肿瘤抑制因子腺瘤如何
大肠杆菌(APC)通过调节 Wnt 受体抑制 Wnt 信号转导通路
复合物(信号体)并展示如何利用它来靶向 APC 突变结直肠
癌症(CRC)。 Wnt 信号对于肠道干细胞的维持至关重要,而异常的
该途径的激活最常通过 APC 突变失活而发生,触发
绝大多数 CRC 的开发。在 Wnt 信号传导的经典模型中,唯一的作用是
APC 的作用是破坏 Wnt 通路中关键转录激活因子 β-catenin 的稳定性。然而,我们的
最近发表的研究结果揭示了一个额外的全新功能——APC 可以防止
信号体的内化和随后的激活,这是进化上的一个新角色
保守的。我们已经证明:1)APC 的诱导性丢失很快就会出现配体依赖性
信号体激活; 2) LRP6(一种信号体)的耗竭或抗体介导的抑制
成分)抑制 β-连环蛋白的稳定、Wnt 靶基因的转录激活,
以及APC突变细胞的增殖; 3) 在APC突变细胞中,Wnt受体的内吞作用是
Wnt 信号传导异常激活所需的。该项目的目标是利用体外、离体、
和体内方法,以更好地了解 APC 如何抑制信号体激活
在生理条件下并确定信号体的异常激活是如何发生的
肿瘤中 APC 失活的后果。这三个具体目标是:1)阐明
APC 丢失促进 CRC 细胞中信号小体组装的机制; 2) 识别APC
突变型 CRC 细胞最容易受到 LRP6 失活的影响; 3)测试LRP6失活的功效
CRC 体内致瘤性。因为 APC 预防的分子机制
Wnt 信号传导的异常激活对于我们理解结直肠癌发生非常重要,
从这项研究中获得的知识将有助于制定新的治疗策略
CRC 和其他 Wnt 驱动的癌症的治疗。
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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Yasmath Ahmed其他文献
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{{ truncateString('Yasmath Ahmed', 18)}}的其他基金
A Cereblon signaling network in Wnt-driven cancers
Wnt 驱动的癌症中的 Cereblon 信号网络
- 批准号:
10670555 - 财政年份:2023
- 资助金额:
$ 65.05万 - 项目类别:
Super-resolution spinning disk confocal microscope for Dartmouth Life Sciences
用于达特茅斯生命科学的超分辨率转盘共焦显微镜
- 批准号:
10427997 - 财政年份:2022
- 资助金额:
$ 65.05万 - 项目类别:
Genetic and Molecular Dissection of Wnt Pathway Activation
Wnt 通路激活的遗传和分子剖析
- 批准号:
10163216 - 财政年份:2020
- 资助金额:
$ 65.05万 - 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
- 批准号:
10063347 - 财政年份:2020
- 资助金额:
$ 65.05万 - 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
- 批准号:
10653134 - 财政年份:2020
- 资助金额:
$ 65.05万 - 项目类别:
Genetic and Molecular Dissection of Wnt Pathway Activation
Wnt 通路激活的遗传和分子剖析
- 批准号:
10417184 - 财政年份:2020
- 资助金额:
$ 65.05万 - 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
- 批准号:
10424450 - 财政年份:2020
- 资助金额:
$ 65.05万 - 项目类别:
Role of ADP-ribosylation in Wnt Pathway Activation
ADP-核糖基化在 Wnt 通路激活中的作用
- 批准号:
9892659 - 财政年份:2017
- 资助金额:
$ 65.05万 - 项目类别:
Role of ADP-ribosylation in Wnt Pathway Activation
ADP-核糖基化在 Wnt 通路激活中的作用
- 批准号:
9383497 - 财政年份:2017
- 资助金额:
$ 65.05万 - 项目类别:
APC Tumor Suppressor in Cell Differentiation and Death
APC 肿瘤抑制因子在细胞分化和死亡中的作用
- 批准号:
9383490 - 财政年份:2017
- 资助金额:
$ 65.05万 - 项目类别:
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