Cellular decoding of signaling dynamics

信号动力学的细胞解码

• 批准号: 10462619
• 负责人: Amir Mitchell
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462619
• 关键词: Automobile Driving; Biological Models; Cell Proliferation; Cell physiology; Cells; Cellular biology; Communities; DNA Sequence Alteration; Decision Making; Development; Disease; Disease Progression; Drug resistance; Environment; Feedback; Functional disorder; Genetic Transcription; Goals; Health; Human body; Malignant Neoplasms; Methodology; Methods; Microscopy; Monitor; Mutation; Oncogenic; Outcome; Pathway interactions; Pattern; Physiologic pulse; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; System; Therapeutic Intervention; Variant; extracellular; in vitro Model; non-genetic; protein phosphatase inhibitor-2; screening; stem; targeted treatment; tumorigenesis

Signaling pathways are fundamental for the ability of cells to correctly respond to extracellular changes and their dysregulation underlies variety of disorders and diseases, most notably cancer. Studies of central signaling pathways revealed that cells encode information in the temporal dynamics of signaling and not just in signaling amplitude. That is, signaling is not merely switched ON or OFF, but is tuned and adjusted to encode meaningful temporal activity profiles (as oscillations, and pulses). This regulated tuning of the core pathway is carried out by a numerous modulator protein that together form a regulatory network of feedback and control loops. A long-standing challenge in cell biology has been to identify the proteins that can modulate temporal profiles of central signaling pathways. Such identification is critical for elucidating cellular decision making in health and its malfunction in disease. A central goal of my lab is to use the well-characterized Ras-Erk pathway as model system to investigate the regulation of signaling dynamics and to uncover their involvement in cancer disease. Multiple studies have substantiated the role of signaling dynamics in this pathway. Yet while much progress was made in elucidating interactions in the core pathway, the understanding of how the surrounding network regulates its dynamics and the role of this type of dysregulation in cancer is lagging far behind. We and others, have recently started to unveil the importance of dysregulation of Ras-Erk dynamics by showing that some oncogenic mutations alter the pathway’s signaling dynamics rather than amplitude. However, while these findings provide a starting point, the high-throughput, systematic study of dysregulation of dynamics remains highly underexplored because of the complexity of monitoring dynamics in live-cells and incompatibility with current screening methods. My lab developed high-throughput microscopy and screening approaches to overcome these technological limitations. We will leverage these platforms to investigate two model in-vitro systems featuring variation in Ras-Erk dynamics: we will investigate the genetic (mutations) mechanisms that underlie unlicensed proliferation (oncogenesis) and non-genetic (transcriptional and signaling states) mechanisms underlying adaptive drug resistance against targeted-therapy. Successful identification of mechanisms underlying Ras-Erk dynamics will both promote the understanding of a very central pathway involved in development and disease and will uncover a new type of targets amenable for therapeutic intervention. These include identifying new mutations driving oncogenesis and uncovering new proteins and interactions that can be targeted to hinder disease progression and drug resistance. Moreover, this research will impact the broad scientific community by demonstrating a strategy and methodology for resolving the intricate connections between signaling dynamics and cell-fate decisions - a connection that emerges as fundamental for many cell decisions and multiple disease.

信号通路是细胞正确响应细胞外变化的能力的基础 它们的失调是各种疾病和疾病的基础，最明显的是癌症。关于中央的研究 信号通路揭示，细胞在信号的时间动力学中编码信息，而不仅仅是在 信号幅度。也就是说，信令不仅被打开或关闭，而且还被调谐和调整以进行编码 有意义的时间活动轮廓(如振荡和脉冲)。这种对核心通路的调节是 由众多的调节蛋白执行，共同形成反馈和控制的调节网络 循环。细胞生物学中的一个长期挑战是识别能够调节时间的蛋白质 中枢信号通路的概况。这种鉴定对于阐明细胞决策是至关重要的。 健康及其在疾病中的故障。我的实验室的一个中心目标是使用表征良好的RAS-ERK途径 作为模型系统来研究信号动力学的调节并揭示它们与癌症的关系 疾病。多项研究证实了信号动力学在这一途径中的作用。然而，虽然很多 在阐明核心通路中的相互作用方面取得了进展，即对周围环境如何 网络调节其动态，而这种类型的失调在癌症中的作用远远落后。 我们和其他人最近开始揭示RAS-ERK动力学失调的重要性 表明一些致癌基因突变改变了通路的信号动力学，而不是幅度。 然而，尽管这些发现提供了一个起点，但对失调的高通量、系统性研究 由于监测活细胞和 与目前的筛查方法不兼容。我的实验室开发了高通量显微镜和筛查 克服这些技术限制的方法。我们将利用这些平台调查两个 以RAS-ERK动力学变异为特征的体外系统模型：我们将研究遗传(突变) 未经许可的增殖(致癌)和非遗传(转录和信号)的机制 各国)对靶向治疗产生适应性抗药性的潜在机制。成功识别 RAS-ERK动力学的潜在机制将促进对非常中心的途径的理解 参与开发和疾病，并将发现一种新的可用于治疗的靶点 干预。这些措施包括识别驱动肿瘤发生的新突变，以及发现新的蛋白质和 可针对阻碍疾病进展和抗药性的相互作用。此外，这项研究还 将通过展示解决问题的战略和方法来影响广大科学界 信号动力学和细胞命运决定之间错综复杂的联系--这种联系表现为 是许多细胞决定和多种疾病的基础。