The role of dynamics in defining the limits of normal developmental signaling.

动力学在定义正常发育信号限制中的作用。

基本信息

  • 批准号:
    9324287
  • 负责人:
  • 金额:
    $ 31.48万
  • 依托单位:
  • 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:
    2016-08-01 至 2021-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Signaling by the Ras/ERK pathway controls cell proliferation, migration, and differentiation. Proper function of this pathway is essential for human development and homeostasis. Sporadic mutations in the pathway play a central role in many cancers, while hereditary mutations cause a series of congenital syndromes, termed RASopathies, which result in impaired cognitive development, cardiac malformations, and increased risk of cancer. A major unanswered question is what differentiates normal from pathological Ras/ERK signaling. It is known that the dynamic pattern of ERK activity - including the strength, frequency, and duration of its activity - are essential to proper signaling. However, the standard methods for measuring ERK activity lack the single-cell precision needed to resolve these essential details. In this project, we will use live-cell imaging, which allows nearl continuous monitoring of thousands of cells simultaneously, to collect data on mutant-driven ERK signaling that is far more accurate and detailed than was previously available. We will focus on the mutations found in the RASopathies, where their role as a single gene driving pathological effects in development is more clearly defined than in cancer, where mutations in many other genes are a complication. We will use our imaging platform to compare for the first time the changes in ERK signaling resulting from disease-causing mutations at the single cell level. Using multiple in vitro systems to replicate cellular processes involved in development, we will determine how these changes modify cell proliferation, migration, and differentiation. We will then dissect the mechanisms underlying these phenotypic changes at the level of gene expression, using a new class of reporters that are integrated directly into the genomes of human cells. At the levels of kinase kinetics, gene expression, and cell behavior, we will quantify how mutant cells respond to multiple Ras pathway inhibitors, which are now being considered as treatments for the RASopathies. This work will have several important outcomes. First, it will reveal the quantitative boundaries of signal behavior that are compatible with normal function, allowing us to understand how Ras pathway mutations lead to disease, and why some mutations are more severe than others. Secondly, it will allow us to make rational choices about which drugs to give to patients with different mutations, so that treatment can be personalized to best normalize each individual's specific signaling patterns. Finally, it will result in a mathematical model of the link between kinase activity and downstream gene expression programs that will allow us to better understand developmental programs and engineer desired cellular responses using existing drugs that target kinase activity.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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John G. Albeck其他文献

Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib
通过抗癌药物 alpelisib 抑制宿主 PI3K,甲型流感病毒基因组缺陷和非感染性颗粒增加
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ilechukwu Agu;Ivy José;A. Ram;D. Oberbauer;John G. Albeck;Samuel L. Díaz Muñoz
  • 通讯作者:
    Samuel L. Díaz Muñoz
Collecting and organizing systematic sets of protein data
收集和组织系统的蛋白质数据集
  • DOI:
    10.1038/nrm2042
  • 发表时间:
    2006-11-01
  • 期刊:
  • 影响因子:
    90.200
  • 作者:
    John G. Albeck;Gavin MacBeath;Forest M. White;Peter K. Sorger;Douglas A. Lauffenburger;Suzanne Gaudet
  • 通讯作者:
    Suzanne Gaudet

John G. Albeck的其他文献

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{{ truncateString('John G. Albeck', 18)}}的其他基金

Decoding temporal epithelial signaling programs to restore homeostasis in acute lung injury
解码颞上皮信号传导程序以恢复急性肺损伤的稳态
  • 批准号:
    10297749
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
Decoding temporal epithelial signaling programs to restore homeostasis in acute lung injury
解码颞上皮信号传导程序以恢复急性肺损伤的稳态
  • 批准号:
    10673694
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
Control of gene expression by dynamic metabolic oscillations
通过动态代谢振荡控制基因表达
  • 批准号:
    10461717
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
Control of gene expression by dynamic metabolic oscillations
通过动态代谢振荡控制基因表达
  • 批准号:
    10668353
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
The role of dynamics in defining the limits of normal developmental signaling
动力学在定义正常发育信号限制中的作用
  • 批准号:
    10390229
  • 财政年份:
    2016
  • 资助金额:
    $ 31.48万
  • 项目类别:
The role of dynamics in defining the limits of normal developmental signaling.
动力学在定义正常发育信号限制中的作用。
  • 批准号:
    9980924
  • 财政年份:
    2016
  • 资助金额:
    $ 31.48万
  • 项目类别:
The role of dynamics in defining the limits of normal developmental signaling.
动力学在定义正常发育信号限制中的作用。
  • 批准号:
    9505933
  • 财政年份:
    2016
  • 资助金额:
    $ 31.48万
  • 项目类别:
The role of dynamics in defining the limits of normal developmental signaling.
动力学在定义正常发育信号限制中的作用。
  • 批准号:
    9893735
  • 财政年份:
    2016
  • 资助金额:
    $ 31.48万
  • 项目类别:

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  • 批准号:
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    25330237
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    $ 31.48万
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    23591741
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