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Chemical Genetic Analysis of RAS Signaling

Chemical Genetic Analysis of RAS Signaling
RAS 信号转导的化学遗传学分析
批准号:
10642578
负责人:
Dustin J Maly
金额:
$4.11万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-04-01 至 2026-02-28

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中文摘要
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英文摘要
Abstract The GTPase RAS functions as a molecular “on/off” switch, existing both in GDP-bound (inactive) and GTP- bound forms (active). Despite functioning as a simple binary switch, RAS is capable of directing complex and diverse cellular processes, including proliferation, migration, survival, and T-cell development. Recent work suggests that the ability of RAS to play complex, often conflicting roles in diverse processes results from differences in cellular context and and/or subcellular localization of its signaling. We have developed a novel chemical genetic tool–called Chemically-Inducible Activator of RAS (CIAR)–to study the dynamics of the signaling networks that are mediated by RAS activity. CIAR allows rapid and dose-dependent activation of RAS signaling with a cell permeable small molecule. With CIAR, we propose to use targeted, quantitative phosphoproteomics and transcriptomics to study the fundamental dynamic behavior of RAS-driven signaling. Subcellularly-localized versions of CIAR will be used to determine the effects of localized RAS activation on the dynamics of RAS-mediated signaling. We will also delineate the interplay between WT RAS and oncogenic RAS signaling and the contribution of WT RAS-mediated signaling to direct inhibitors of oncogenic RAS mutants. Finally, we will develop and use a chemically-controlled toolset for the rapid activation of signaling enzyme oligomers, which will be used to dissect the role that oligomerization state plays in RAS signaling dynamics.
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Chemical Genetic Analysis of RAS Signaling
  • 批准号:
    10589943
  • 项目类别:
  • 资助金额:
    $32.78万
  • 财政年份:
    2022
  • 负责人:
    Dustin J Maly
  • 依托单位:
Chemical Genetic Analysis of RAS Signaling
  • 批准号:
    10728391
  • 项目类别:
  • 资助金额:
    $8.22万
  • 财政年份:
    2022
  • 负责人:
    Dustin J Maly
  • 依托单位:
Partial Antagonists of IRE1 RNaseââPAIRâsâto treat Type 1 Diabetes
Partial Antagonists of IRE1 RNase--'PAIR's--to treat Type 1 Diabetes
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