Cellular decoding of signaling dynamics

信号通路是细胞正确响应细胞外变化的能力的基础， 它们的失调是各种紊乱和疾病，最显著的是癌症的基础。中央研究 信号通路揭示了细胞在信号传导的时间动态中编码信息，而不仅仅是在 信号幅度也就是说，信令不仅被打开或关闭，而且被调谐和调整以编码 有意义的时间活动曲线（如振荡和脉冲）。这种对核心途径的调节是 这些调节蛋白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鉴定能够调节时间依赖性的蛋白质。 中央信号通路的概况。这种识别对于阐明细胞决策至关重要， 健康及其在疾病中的功能障碍。我的实验室的一个中心目标是使用特征鲜明的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 疾病多项研究已经证实了信号动力学在这一途径中的作用。然而，尽管许多 在阐明核心途径的相互作用方面取得了进展， 网络调节其动态，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， 这表明一些致癌突变改变了该途径的信号动力学而不是幅度。 然而，虽然这些发现提供了一个起点，高通量，系统的研究失调， 由于在活细胞中监测动态的复杂性， 与现有的筛选方法不兼容。我的实验室开发了高通量显微镜和筛选 克服这些技术限制的方法。我们将利用这些平台调查两个 模型在体外系统具有Ras-Erk动态变化：我们将研究遗传（突变） 未经许可的增殖（肿瘤发生）和非遗传（转录和信号传导）的基础机制 国家）机制的适应性耐药靶向治疗。成功识别 Ras-Erk动力学的潜在机制将促进对一个非常核心的途径的理解， 参与发展和疾病，并将发现一种新的类型的目标适用于治疗 干预这些研究包括识别驱动肿瘤发生的新突变和发现新的蛋白质， 可以有针对性地阻碍疾病进展和耐药性的相互作用。此外，这项研究 将通过展示解决这些问题的战略和方法来影响广大的科学界。 信号动力学和细胞命运决定之间的复杂联系-这种联系出现在 是许多细胞决定和多种疾病的基础。

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.