Rewiring the miRNA-MDM2-p53 network to reactivate p53 function
重新连接 miRNA-MDM2-p53 网络以重新激活 p53 功能
基本信息
- 批准号:8507664
- 负责人:
- 金额:$ 18.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressApoptosisBasic Cancer ResearchBiochemicalBiological SciencesBudgetsCell Cycle ArrestCell physiologyCellsCellular Stress ResponseComplexComputer SimulationCoupledDNADetectionDevelopmentDiagnosisDiseaseDoctor of PhilosophyDrug TargetingElectrical EngineeringEngineeringEnvironmental Risk FactorFeedbackGenesGenome StabilityHealthHeartHomeostasisHumanIndividualInterventionKnowledgeLeadLifeLightMDM2 geneMalignant NeoplasmsMathematicsMedicalMedicineMethodsMicroRNAsModalityMolecularPathway interactionsPatientsPlayPrincipal InvestigatorProcessPropertyProtein p53ProteinsRNAReactionRegulationResearchResolutionRoleSignal PathwaySignal TransductionSignal Transduction PathwayStressSystemSystems BiologyTimeTrainingTreatment-Related CancerTumor SuppressionVesicleWorkbasebiological adaptation to stresscancer initiationcancer preventioncancer therapydesignenvironmental changeexperiencein vivoinhibitor/antagonistinnovationinsightlaboratory facilitymathematical modelmeetingsmodels and simulationmolecular scalenovelpreventresearch studyresponsesenescencesensorsmall moleculesynthetic biologytheoriestooltranscription factortumor
项目摘要
DESCRIPTION (provided by applicant): The ability of signaling networks to detect, process, and react specifically to various stress signals is a key property of living cells. To characterize
these oftentimes overwhelmingly complex signal transduction pathways, one promising approach is to use quantitative experiments in synergy with modeling and simulations. We focus on the network underlying the stress response of p53, a pivotal player in cancer initiation and prevention aside from its contribution to numerous other aspects of disease and normal life. Lying at the heart of intricate regulations is the autoregulatory feedback of p53 by MDM2, a critical negative regulator of p53. As most human malignancies shut down the p53 tumor-suppressing responses to survive, p53 and MDM2 are of the most promising targets for drug intervention in cancer therapy. Meanwhile, microRNAs (miRNAs) have emerged as a key regulatory player in nearly every cellular process and intriguingly recent studies show that miRNAs have direct interactions with the p53-MDM2 core. It is safe to assume that the coupled pathways formed by miRNAs and p53-MDM2 play a fundamental role in cellular health. We propose to develop novel methods to theoretically assess the interactions between p53-MDM2 and miRNAs, and experimentally rewire the miRNA-p53-MDM2 network. We propose the experimental implementation of novel molecular circuits engineered to respond to microRNAs introducing closed-loop feedback control to revive the p53 function. We believe that our proposal can provide new insight to medical strategies in the treatment of p53-dependent human cancers.
描述(由申请人提供):信号网络检测、处理和对各种应激信号做出特异性反应的能力是活细胞的关键特性。表征
对于这些通常极其复杂的信号转导途径,一种有前途的方法是使用定量实验与建模和模拟相结合。我们重点关注 p53 应激反应背后的网络,p53 除了对疾病和正常生活的许多其他方面做出贡献之外,在癌症发生和预防中也发挥着关键作用。复杂调控的核心是 MDM2(p53 的关键负调节因子)对 p53 的自动调节反馈。由于大多数人类恶性肿瘤为了生存而关闭 p53 肿瘤抑制反应,因此 p53 和 MDM2 是癌症治疗中药物干预最有希望的靶点。与此同时,microRNA (miRNA) 已成为几乎所有细胞过程中的关键调控因子,有趣的是,最近的研究表明 miRNA 与 p53-MDM2 核心具有直接相互作用。可以肯定的是,miRNA 和 p53-MDM2 形成的耦合途径在细胞健康中发挥着重要作用。我们建议开发新方法来从理论上评估 p53-MDM2 和 miRNA 之间的相互作用,并通过实验重新连接 miRNA-p53-MDM2 网络。我们建议实验性地实施新型分子电路,该电路被设计用于响应 microRNA,引入闭环反馈控制来恢复 p53 功能。我们相信,我们的建议可以为治疗 p53 依赖性人类癌症的医学策略提供新的见解。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Guide RNA engineering for versatile Cas9 functionality.
- DOI:10.1093/nar/gkw908
- 发表时间:2016-11-16
- 期刊:
- 影响因子:14.9
- 作者:Nowak CM;Lawson S;Zerez M;Bleris L
- 通讯作者:Bleris L
MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells.
- DOI:10.1371/journal.pcbi.1004653
- 发表时间:2015-12
- 期刊:
- 影响因子:4.3
- 作者:Moore R;Ooi HK;Kang T;Bleris L;Ma L
- 通讯作者:Ma L
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Leonidas Bleris其他文献
Leonidas Bleris的其他文献
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{{ truncateString('Leonidas Bleris', 18)}}的其他基金
Rewiring the miRNA-MDM2-p53 network to reactivate p53 function
重新连接 miRNA-MDM2-p53 网络以重新激活 p53 功能
- 批准号:
8364777 - 财政年份:2012
- 资助金额:
$ 18.77万 - 项目类别:
Reverse Engineering of Direct versus Indirect Effects in Biological Pathways
生物途径中直接效应与间接效应的逆向工程
- 批准号:
8320178 - 财政年份:2011
- 资助金额:
$ 18.77万 - 项目类别:
Probing the characteristics of genetic circuits integrated in mammalian cells and
探究哺乳动物细胞中整合的遗传电路的特征
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8180749 - 财政年份:2011
- 资助金额:
$ 18.77万 - 项目类别:
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