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Cellular decoding of signaling dynamics

信号动力学的细胞解码

基本信息

批准号：
10684247
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
项目类别：
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

项目摘要

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基础