Negative and positive feedback in cell signaling

细胞信号传导的负反馈和正反馈

基本信息

批准号：
9916756
负责人：
Henrik G. Dohlman
金额：
$ 65.34万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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

项目摘要

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信号有了很多了解。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转录因子等下游靶标，从而驱动新的基因转录。通过这种方式，一些信号被放大，而另一些信号则被放大。负反馈的常见例子包括对气味、光和许多药物的脱敏，除了过去的工作集中于导致脱敏的反馈抑制之外，我们提出的工作将集中于反馈调节的三个额外的重要后果：I：信号协调；例如限制竞争激酶途径的不适当激活；例如将分级输入转换为类似开关的输出，或者反之亦然。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，这些激酶会响应各种（通常是竞争性）刺激而被激活，其中包括激素、压力和细胞因子。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。由于新的微流体装置能够跟踪单细胞中的通路活性，并确定这些磷酸化事件的后果，因此我们的研究将需要多轮数据收集、模型构建和模型测试。和模型细化，因此将大大受益于 R35 拨款机制提供的灵活性和稳定性。