Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)
Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)
批准号:
10402163
负责人:
ETHAN LEE
金额:
$56.27万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
未结题
起止时间:
2017-04-01 至 2027-03-31
关键词:
AdultAgonistAwardBehaviorBiochemicalBiological ProcessCSNK1A1 geneCell MaintenanceCellsClinical TrialsColorectal CancerComplexDefectDevelopmentDiseaseDrug TargetingEmbryonic DevelopmentFDA approvedFamilial Adenomatous Polyposis SyndromeFinancial compensationGenetic TranscriptionGoalsHumanLeadMalignant NeoplasmsMediatingModelingMolecularMutationNuclearOrphan DrugsPathway interactionsPharmaceutical PreparationsPlayProteinsReceptor ActivationRegulationResearchResearch PersonnelRoleSignal TransductionSystemTumor Suppressor ProteinsWNT Signaling PathwayWorkXenopusadult stem celleggmathematical modelmutantpremalignantreceptorreconstitutionsmall molecule inhibitorstem cellsubiquitin-protein ligase
中文摘要
项目总结:
进化上保守的Wnt途径在后生动物的发育过程中起着关键作用
以及成人体内干细胞的维持。导致ITS的Wnt途径的突变
人类的错误调节已被证明是导致发育缺陷和
癌症。在后一种情况下,超过90%的非遗传性结直肠癌是
由Wnt途径的突变启动,导致其不适当的激活。没有
FDA批准的抑制Wnt途径的药物,这可能是由于我们的不完全
了解Wnt信号转导机制,缺乏合适的药物靶点。这个
我的实验室主要关注的是通过以下方式了解Wnt信号通路的生物学功能
破译其分子机制,鉴定新的Wnt组分。我们的最终目标是
为了利用这些信息来理解WNT途径的放松调控如何导致WNT-
由人类引发的疾病。
十多年来,我的实验室为我们的基础工作做出了重大贡献
了解Wnt信号。这些突破是通过发展实现的
对第一生化系统(使用非洲爪蛙卵提取液)的重组进行了活性纯化
蛋白质,第一个数学模型(Lee-Heinrich模型)的发展,以及
鉴定小分子抑制剂(CK1激动剂),其中一种已被指定为
FDA作为一种家族性癌前疾病(家族性腺瘤)的孤儿药物
息肉病)。
我们目前的工作集中在确定USP46/UAF1/WDR20去泛素酶的作用
调节LRP6受体周转的复合体--APC调节Wnt的机制
受体活性、-连环蛋白降解复合体在介导双稳态途径中的作用
行为,以及USP47和STK38在调节Wnt信号中的作用。在我们的更新中
应用,我们现在建议:1)重建LRP6泛素化并鉴定其进化
保守的E3连接酶,2)了解Wnt受体缺失的信号补偿基础
APC突变细胞,3)为双稳在形态发生中的作用提供证据
4)揭示STK38和TRIP12在核Wnt信号转导中的作用。
英文摘要
PROJECT SUMMARY:
The evolutionarily conserved Wnt pathway plays a critical role during metazoan development
and stem cell maintenance in the adult. Mutations in the Wnt pathway leading to its
misregulation in humans have been shown to contributes to both developmental defects and
cancers. In the latter case, over 90% of all non-hereditary forms of colorectal cancers are
initiated by mutations in the Wnt pathway leading to its inappropriate activation. There are no
FDA-approved drugs that inhibit the Wnt pathway, which is likely due to our incomplete
understanding of the mechanism of Wnt signaling and the lack of suitable drug targets. The
primary focus of my lab is to understand the biological function of the Wnt signaling pathway by
deciphering its molecular mechanism and identifying new Wnt components. Our ultimate goal is
to use this information to understand how deregulation of the Wnt pathway can lead to Wnt-
driven diseases in humans.
Over more than a decade, my lab has made significant contributions to our fundamental
understanding of Wnt signaling. These breakthroughs were accomplished via the development
of the first biochemical system (using Xenopus egg extract), the reconstitution of active purified
proteins, the development of the first mathematical model (Lee-Heinrich model), and the
identification of small molecule inhibitors (CK1 agonists), one of which has been designated by
the FDA as an orphan drug for a familial precancerous disease (familial adenomatous
polyposis).
Our current work focused on determining the role of the USP46/UAF1/WDR20 deubiquitinase
complex in regulating LRP6 receptor turnover, the mechanism by which APC regulates Wnt
receptor activity, the role of the -catenin degradation complex in mediating bistable pathway
behavior, and the roles of USP47 and STK38, in regulating Wnt signaling. In our renewal
application, we now propose to 1) reconstitute LRP6 ubiquitylation and identify its evolutionarily
conserved E3 ligase, 2) understand the basis for signal compensation upon Wnt receptor loss in
APC mutant cells, 3) provide evidence for the role of bistability in generating morphogenetic
signaling, and 4) uncover the roles of the STK38 and TRIP12 in nuclear Wnt signaling.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mechanism of Wnt signal transduction
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批准号:9905536
-
项目类别:
-
资助金额:$59.06万
-
财政年份:2017
-
负责人:ETHAN LEE
-
依托单位:
Mechanism of Wnt signal transduction
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批准号:9519127
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项目类别:
-
资助金额:$21.25万
-
财政年份:2017
-
负责人:ETHAN LEE
-
依托单位:
Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)
-
批准号:10791528
-
项目类别:
-
资助金额:$9.41万
-
财政年份:2017
-
负责人:ETHAN LEE
-
依托单位:
Maximizing Investigators' Research Award (R35 - Clinical Trial Optional)
-
批准号:10596608
-
项目类别:
-
资助金额:$56.27万
-
财政年份:2017
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负责人:ETHAN LEE
-
依托单位:
Role of ubiquitination in the Wnt pathway
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批准号:8667484
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项目类别:
-
资助金额:$29.76万
-
财政年份:2013
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负责人:ETHAN LEE
-
依托单位:
Role of ubiquitination in the Wnt pathway
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批准号:8417128
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项目类别:
-
资助金额:$29.61万
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财政年份:2013
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负责人:ETHAN LEE
-
依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:7939072
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项目类别:
-
资助金额:$5.91万
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财政年份:2009
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负责人:ETHAN LEE
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依托单位:
Regulation of beta-catenin degradation during Wnt signal transduction
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批准号:8437474
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项目类别:
-
资助金额:$29.65万
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财政年份:2007
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负责人:ETHAN LEE
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依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:7825257
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项目类别:
-
资助金额:$23.09万
-
财政年份:2007
-
负责人:ETHAN LEE
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依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:7455949
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项目类别:
-
资助金额:$23.32万
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财政年份:2007
-
负责人:ETHAN LEE
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依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:7619172
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项目类别:
-
资助金额:$23.32万
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财政年份:2007
-
负责人:ETHAN LEE
-
依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:7296538
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项目类别:
-
资助金额:$23.32万
-
财政年份:2007
-
负责人:ETHAN LEE
-
依托单位:
Regulation of beta-catenin degradation during Wnt signal transduction
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批准号:9124891
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项目类别:
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资助金额:$29.8万
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财政年份:2007
-
负责人:ETHAN LEE
-
依托单位:
Biochemical reconstitution of heterotrimeric G proteins in the Wnt pathway
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批准号:8067849
-
项目类别:
-
资助金额:$22.86万
-
财政年份:2007
-
负责人:ETHAN LEE
-
依托单位:
Regulation of beta-catenin degradation during Wnt signal transduction
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批准号:8916772
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项目类别:
-
资助金额:$29.8万
-
财政年份:2007
-
负责人:ETHAN LEE
-
依托单位:
Regulation of beta-catenin degradation during Wnt signal transduction
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批准号:8740496
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项目类别:
-
资助金额:$29.8万
-
财政年份:2007
-
负责人:ETHAN LEE
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依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: