Negative and positive feedback in cell signaling

细胞信号传导的负反馈和正反馈

• 批准号: 9267158
• 负责人: Henrik G. Dohlman
• 金额: $ 54.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267158
• 关键词: Biological; Cell membrane; Cells; Chemicals; Computer Simulation; Cues; Cyclic AMP-Dependent Protein Kinases; Data Collection; Drug Combinations; Environment; Event; Feedback; Genetic Transcription; Grant; Hormones; Investigation; Light; Microfluidic Microchips; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neurotransmitters; Odors; Output; Partner in relationship; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Physiological; Protein Kinase; Regulation; Saccharomyces cerevisiae; Scientist; Signal Transduction; Stimulus; Stress; Testing; Transducers; Work; Yeasts; biological adaptation to stress; cell growth; cell motility; cytokine; desensitization; flexibility; model building; new therapeutic target; public health relevance; receptor; response; sensor; transcription factor

 DESCRIPTION (provided by applicant): Over the past half century scientists have learned much about how cells detect physical and chemical cues in their environment. Typically, cell signaling requires a plasma membrane receptor, an intracellular transducer and a downstream effector such as a protein kinase. Protein kinases are well known to phosphorylate downstream targets such as transcription factors, which drive new gene transcription. Most kinases also phosphorylate upstream components leading to positive or negative feedback. In this way, some signals become amplified while others become diminished. Familiar examples of negative feedback include desensitization to odors, light, and many pharmaceuticals. Whereas past work has focused on feedback inhibition leading to desensitization, our proposed work will focus on three additional and important consequences of feedback regulation: I: Signal coordination; for example to limit inappropriate activation of a competing kinase pathway. II: Signal tuning; for example to convert a graded input to a switch-like output, or vice versa. III: Signal tracking; for example to allow cell growth or migration towards a gradient stimulus. Our investigation will center on the mitogen activated protein kinases (MAPKs), which are activated in response to diverse (and often competing) stimuli including hormones, stresses and cytokines. Among the best- characterized MAPK pathways are those found in yeast Saccharomyces cerevisiae, where they contribute to cell mating and the osmotic stress response. Our approach will capitalize on recent breakthroughs, including newer fluorescent sensors capable of tracking biological responses, as well as new microfluidics devices capable of tracking pathway activity in single cells. Comprehensive identification of MAPK substrates, and establishing the consequences of those phosphorylation events, will inform new predictive computational models. Our investigations will require multiple rounds of data collection, model building, model testing, and model refinement, and would therefore benefit greatly from the flexibility and stability provided by the R35 grant mechanism.

 描述（由申请人提供）：在过去的半个世纪中，科学家们对细胞如何检测环境中的物理和化学线索有了很多了解。通常，细胞信号传导需要质膜受体、细胞内转导器和下游效应器（例如蛋白激酶）。众所周知，蛋白激酶可以磷酸化下游靶标，例如驱动新基因转录的转录因子。大多数激酶还会磷酸化上游成分，从而导致正反馈或负反馈。通过这种方式，一些信号被放大，而另一些信号被减弱。负反馈的常见例子包括对气味、光和许多药物不敏感。虽然过去的工作重点是导致脱敏的反馈抑制，但我们提出的工作将重点关注反馈调节的三个额外的重要后果：I：信号协调；例如，限制竞争性激酶途径的不当激活。 II：信号调谐；例如，将分级输入转换为类似开关的输出，反之亦然。 III：信号跟踪；为了 例如允许细胞向梯度刺激生长或迁移。我们的研究将集中在丝裂原激活蛋白激酶 (MAPK) 上，该激酶会响应多种（通常是竞争性）刺激而被激活，包括激素、压力和细胞因子。最典型的 MAPK 途径是在酿酒酵母中发现的途径，它们有助于细胞交配和渗透应激反应。我们的方法将利用最近的突破，包括能够跟踪生物反应的新型荧光传感器，以及能够跟踪单细胞通路活动的新型微流体设备。 MAPK 底物的全面鉴定，并确定这些磷酸化事件的后果，将为新的预测计算模型提供信息。我们的调查需要多轮数据收集、模型构建、模型测试和模型细化，因此将大大受益于 R35 资助机制提供的灵活性和稳定性。