The Role of IKK and NF-kappaB in Controlling mTOR Signaling and TSC Progression
IKK 和 NF-kappaB 在控制 mTOR 信号传导和 TSC 进展中的作用
基本信息
- 批准号:8735087
- 负责人:
- 金额:$ 23.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-16 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnimalsBenignBiochemicalBrainCell Cycle ProgressionCell SurvivalCellsChronicClinical TrialsComplexDataDevelopmentDiseaseFeedbackGeneticGoalsGrowthHeartHumanKidneyKnock-outLeadLesionLinkLungMusMutagenesisMutationNF-kappa BNull LymphocytesOncogenicOrganPC3 cell linePTEN genePathogenesisPathway interactionsPhosphotransferasesPlayProcessPublishingRegulationRoleSerineSignal PathwaySignal TransductionSirolimusSkinSyndromeTSC1 geneTSC1/2 geneTSC2 geneTestingTissuesTuberous sclerosis protein complexTumor Suppressor Genesabstractingbasecancer cellcell growthefficacy testinggenetic regulatory proteinin vitro Assayinhibitor/antagonistinsightmTOR proteinnew therapeutic targetnovelpalliativereconstitutionresearch studytranscription factortreatment strategytumor
项目摘要
Project Abstract
Tuberous sclerosis complex (TSC) is a human syndrome characterized by widespread
development of benign tumors in a variety of organs including skin, brain, lung, heart and
kidney. TSC is caused by mutation in either the TSC1 or TSC2 gene. Recent studies have
indicated that TSC1 and TSC2 suppress the mammalian target of rapamycin (mTOR) signaling
pathway to control cell growth; thus, abnormal activation of mTOR signaling as a result of
mutation in TSC1 or TSC2 gene may underlie the pathogenesis of TSC. While mechanisms
associated with mTOR regulation and with mTOR downstream effects have been partly
characterized, much is still unknown regarding these mechanisms. Importantly, treatment of
TSC is palliative and no effective cure is known. We have recently found that the IKK complex
(key upstream regulator of the transcription factor NF-kB) interacts with the mTOR complex and
significantly increases both mTORC1 and mTORC2 activity. Additionally, our results revealed
that mTOR controls IKK/NF-NF-kB activation reciprocally. These results implicate IKK/NF-
kappaB pathway as a novel regulator of TSC/mTOR signaling pathway. My data also
demonstrate that both TSC2 and rapamycin regulate IKK/NF-kB activity through mTORC1 in an
Akt-dependent manner. Based on my published studies and preliminary data, I hypothesize
that IKK and NF-kB are critical regulators and effectors for mTOR and Akt in controlling the
progression of TSC, and that rapamycin in combination with an IKK inhibitor could effectively
block the activity of mTOR, Akt and IKK/NF-:B and ultimately block progression of TSC in TSC
animal models. I will characterize the mechanism whereby IKKα controls TORC1 and mTORC2
activity in several cancer cells and in TSC2 -/- MEF cells. I will extensively examine how TSC2
and rapamycin, in combination with an IKK inhibitor, affect NF-kB activity and TSC progression
in cells and TSC animal models. The goal of this proposal is to achieve a mechanistic
understanding of the interaction between IKK/NF-kB and mTOR pathways in promoting cell
survival and growth, and progression of TSC. The proposed genetic and biochemical analyses
and animal model studies will provide novel insight into the regulation and function of
TSC/mTOR and IKK/NF-kB pathways, and the progression of TSC. Further studies could lead
to the identification of new therapeutic targets and ultimately help develop rational, mechanism-
based treatment strategies that target TSC and TSC-related tumors.
项目摘要
多发性硬化症(TSC)是一种人类综合征,其特征在于广泛的
在包括皮肤、脑、肺、心脏在内的多种器官中发展良性肿瘤,
肾TSC由TSC 1或TSC 2基因突变引起。最近的研究
表明TSC 1和TSC 2抑制哺乳动物雷帕霉素靶蛋白(mTOR)信号传导
因此,作为细胞生长的结果,mTOR信号传导的异常激活
TSC 1或TSC 2基因突变可能是TSC发病的基础。虽然机制
与mTOR调节和mTOR下游效应相关的部分
尽管这些机制已经被描述,但仍有许多关于这些机制的未知之处。重要的是,治疗
TSC是姑息性的,目前还没有有效的治疗方法。我们最近发现IKK复合体
(key转录因子NF-κ B的上游调节子)与mTOR复合物相互作用,
显著增加mTORC 1和mTORC 2活性。此外,我们的结果显示,
mTOR调控IKK/NF-NF-kB的活化。这些结果暗示IKK/NF-
kappaB通路作为TSC/mTOR信号通路的新调节剂。我的数据也
证明TSC 2和雷帕霉素都通过mTORC 1调节IKK/NF-κ B活性,
依赖Akt的方式。根据我发表的研究和初步数据,我假设
IKK和NF-kB是mTOR和Akt在控制细胞凋亡中的关键调节因子和效应因子。
TSC的进展,并且雷帕霉素与IKK抑制剂组合可以有效地
阻断mTOR、Akt和IKK/NF-:B的活性,并最终阻断TSC在TSC中的进展
动物模型我将描述IKKα控制TORC 1和mTORC 2的机制
在几种癌细胞和TSC 2-/- MEF细胞中的活性。我将深入研究TSC 2
和雷帕霉素与IKK抑制剂联合影响NF-κ B活性和TSC进展
在细胞和TSC动物模型中。该提案的目标是实现一种机械化的
了解IKK/NF-kB和mTOR通路在促进细胞凋亡中的相互作用
TSC的存活和生长以及进展。建议的遗传和生化分析
动物模型的研究将提供新的见解的调节和功能,
TSC/mTOR和IKK/NF-kB通路,以及TSC的进展。进一步的研究可能会导致
识别新的治疗靶点,并最终帮助开发合理的机制-
针对TSC和TSC相关肿瘤的治疗策略。
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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{{ truncateString('Hancai Dan', 18)}}的其他基金
Inhibition of castration resistant prostate cancer by targeting of the IKKbeta/AR signaling
通过靶向 IKKbeta/AR 信号传导抑制去势抵抗性前列腺癌
- 批准号:
10082436 - 财政年份:2017
- 资助金额:
$ 23.66万 - 项目类别:
Inhibition of castration resistant prostate cancer by targeting of the IKKbeta/AR signaling
通过靶向 IKKbeta/AR 信号传导抑制去势抵抗性前列腺癌
- 批准号:
9216224 - 财政年份:2017
- 资助金额:
$ 23.66万 - 项目类别:
The Role of IKK and NF-kappaB in Controlling mTOR Signaling and TSC Progression
IKK 和 NF-kappaB 在控制 mTOR 信号传导和 TSC 进展中的作用
- 批准号:
8733784 - 财政年份:2013
- 资助金额:
$ 23.66万 - 项目类别:
The Role of IKK and NF-kappaB in Controlling mTOR Signaling and TSC Progression
IKK 和 NF-kappaB 在控制 mTOR 信号传导和 TSC 进展中的作用
- 批准号:
8334000 - 财政年份:2011
- 资助金额:
$ 23.66万 - 项目类别:
The Role of IKK and NF-kappaB in Controlling mTOR Signaling and TSC Progression
IKK 和 NF-kappaB 在控制 mTOR 信号传导和 TSC 进展中的作用
- 批准号:
8045164 - 财政年份:2011
- 资助金额:
$ 23.66万 - 项目类别:
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