Systems Biology of Molecular Noise in Yeast
酵母分子噪声的系统生物学
基本信息
- 批准号:8037216
- 负责人:
- 金额:$ 28.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelBehaviorBindingBiologicalBiological ModelsCell Differentiation processCellsCollaborationsCollectionComplexComputer SimulationCuesDNA Binding DomainDataEngineeringEnvironmentEventFailureFeedbackFlow CytometryGene ExpressionGenerationsGenesGeneticGenetic CrossesGenetic DeterminismGoalsGrowthHealthHeterogeneityHumanHuman EngineeringIndividualKnock-outLeadLinkMAP Kinase GeneMalignant NeoplasmsMeasurementMethodsMitogen-Activated Protein KinasesModelingMolecularMolecular BiologyMolecular ModelsNoiseOrganismOutcomeOutputPartner in relationshipPathway interactionsPhenotypePheromoneReporterRoleSaccharomyces cerevisiaeSaccharomycetalesShapesSignal TransductionSystemSystems BiologyTestingTherapeutic InterventionTimeTranscription CoactivatorWorkYeastsbasedesignextracellularfitnessinhibitor/antagonistmolecular modelingmutantnovelpreventpromoterresearch studyresponsetheoriestumor progression
项目摘要
DESCRIPTION (provided by applicant): Proper assessment by cells of extracellular cues is essential for the normal functioning of all organisms. However, the ability of cells to respond properly to their environment is limited by biological variability or "noise" in the responses of individual cells. This is true of even genetically identical cells in a homogenous environment. Our global hypothesis is that there exist genetically-encoded cellular control systems akin to those used in human-engineered systems that modulate noise and shape phenotypic outcomes, particularly in complex cellular circuits involved in cell differentiation. We seek to test this hypothesis through a combination of i) theory- guided directed experiments, and ii) high-throughput forward genetics that exploit precise measurements of individual cell phenotypes. As a model system, we have chosen the pheromone response differentiation pathway of the budding yeast Saccharomyces cerevisiae, which offers numerous experimental advantages. We seek to continue an already-productive collaboration that brings together theoretical expertise in engineering control systems and stochastic theories with expertise in high-throughput model organism genetics and molecular biology. To achieve our goals, we will build on substantial preliminary work to 1) understand the mechanism of noise suppression by an inhibitor of the pheromone pathway MAP kinase- responsive transcriptional activator, 2) identify the genetic determinants of noise modulation during pheromone signaling, and 3) test the hypothesis that multiple feedback controls act as a system to prevent catastrophic signal transduction events. Together these systems-level studies will reveal the genetic mechanisms by which cells control molecular noise to achieve responses that are quantitatively reproducible. PUBLIC HEALTH RELEVANCE: Given the central role of MAP kinase signaling in human cancers, understanding the mechanisms of noise suppression within a MAPK signaling cascade may impact our understanding of tumor progression and heterogeneity while exposing weak links in the system for therapeutic intervention.
描述(由申请人提供):细胞对细胞外信号的正确评估对于所有生物体的正常功能至关重要。然而,细胞对环境做出适当反应的能力受到个体细胞反应中的生物变异性或“噪音”的限制。即使是在同质环境中的基因相同的细胞也是如此。我们的总体假设是,存在类似于人类工程系统中使用的基因编码的细胞控制系统,其调节噪声并形成表型结果,特别是在涉及细胞分化的复杂细胞回路中。我们试图通过i)理论指导的定向实验和ii)利用个体细胞表型的精确测量的高通量正向遗传学的组合来测试该假设。作为一个模型系统,我们选择了信息素反应分化途径的芽殖酵母酿酒酵母,它提供了许多实验优势。我们寻求继续已经富有成效的合作,将工程控制系统和随机理论的理论专业知识与高通量模式生物遗传学和分子生物学的专业知识结合起来。为了实现我们的目标,我们将建立在大量的初步工作,以1)了解信息素途径MAP激酶响应转录激活因子的抑制剂抑制噪声的机制,2)确定信息素信号传导过程中噪声调制的遗传决定因素,和3)测试多个反馈控制作为一个系统,以防止灾难性的信号转导事件的假设。这些系统水平的研究将揭示细胞控制分子噪音以实现定量可重复响应的遗传机制。公共卫生关系:鉴于MAP激酶信号在人类癌症中的核心作用,理解MAPK信号级联中的噪声抑制机制可能会影响我们对肿瘤进展和异质性的理解,同时暴露系统中的薄弱环节进行治疗干预。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Hana El-Samad其他文献
Hana El-Samad的其他文献
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{{ truncateString('Hana El-Samad', 18)}}的其他基金
Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors
驱动治疗性 T 细胞浸润至免疫冷肿瘤的合成回路
- 批准号:
10487572 - 财政年份:2021
- 资助金额:
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Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors
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10329255 - 财政年份:2021
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Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors
驱动治疗性 T 细胞浸润至免疫冷肿瘤的合成回路
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Unraveling the quantitative dynamics of cAMP-PKA signaling in yeast
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