Chemical Genetic Analysis of RAS Signaling
Chemical Genetic Analysis of RAS Signaling
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
关键词:
BehaviorCell physiologyCellsChemicalsComplexConflict (Psychology)DoseEnvironmentEnzymesEukaryotaGTP BindingGuanosine Triphosphate PhosphohydrolasesMalignant NeoplasmsMediatingMolecularOncogenicPermeabilityPlayProcessRoleSignal TransductionT-Cell DevelopmentWorkchemical geneticsgenetic analysisinhibitormigrationmutantnovelphosphoproteomicssmall moleculetooltranscriptomics
中文摘要
摘要
GT-RAS作为分子"开/关"开关发挥作用,存在于GDP结合(无活性)和GTP结合(无活性)中。
绑定表单(活动)。尽管作为一个简单的二进制开关,RAS是能够指导复杂的,
不同的细胞过程,包括增殖、迁移、存活和T细胞发育。最近的工作
表明RAS在不同过程中扮演复杂的、经常相互冲突的角色的能力来自于
细胞环境和/或其信号传导的亚细胞定位的差异。我们已经开发出一种新颖
化学遗传工具-称为RAS的化学诱导激活剂(CIAR)-研究RAS的动力学。
RAS活性介导的信号网络。CIAR允许快速和剂量依赖性激活
RAS信号转导与细胞可渗透的小分子。通过CIAR,我们建议使用有针对性的,定量的
磷酸蛋白质组学和转录组学研究RAS驱动的信号传导的基本动态行为。
将使用亚细胞定位的CIAR版本来确定局部RAS激活对细胞凋亡的影响。
RAS介导的信号传导的动力学。我们还将描述WT RAS和致癌性RAS之间的相互作用。
RAS信号传导和WT RAS介导的信号传导对致癌RAS直接抑制剂的贡献
变种人最后,我们将开发和使用一个化学控制的工具集,用于快速激活信号
酶寡聚体,这将用于剖析的作用,寡聚状态发挥RAS信号
动力学
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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
-
批准号:10239016
-
项目类别:
-
资助金额:$72.69万
-
财政年份:2019
-
负责人:Dustin J Maly
-
依托单位:
Partial Antagonists of IRE1 RNase--'PAIR's--to treat Type 1 Diabetes
-
批准号:10451643
-
项目类别:
-
资助金额:$72.09万
-
财政年份:2019
-
负责人:Dustin J Maly
-
依托单位:
Partial Antagonists of IRE1 RNaseââPAIRâsâto treat Type 1 Diabetes
-
批准号:10018909
-
项目类别:
-
资助金额:$73.28万
-
财政年份:2019
-
负责人:Dustin J Maly
-
依托单位:
Pharmacological Validation of IRE1 for Diabetes Mellitus
-
批准号:9199585
-
项目类别:
-
资助金额:$53.92万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Target identification by small-molecule labeling in live cells
-
批准号:8680550
-
项目类别:
-
资助金额:$23.18万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Target identification by small-molecule labeling in live cells
-
批准号:8808761
-
项目类别:
-
资助金额:$19.31万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Pharmacological Validation of IRE1 for Diabetes Mellitus
-
批准号:8988567
-
项目类别:
-
资助金额:$48.94万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Discovery and validation of new kinase drug targets in T. brucei
-
批准号:9110190
-
项目类别:
-
资助金额:$40.45万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Discovery and validation of new kinase drug targets in T. brucei
-
批准号:9308827
-
项目类别:
-
资助金额:$40.73万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Pharmacological Validation of IRE1 for Diabetes Mellitus
-
批准号:8614223
-
项目类别:
-
资助金额:$50.2万
-
财政年份:2014
-
负责人:Dustin J Maly
-
依托单位:
Kinase Profiling with Quantititative Chemoproteomics
-
批准号:8546539
-
项目类别:
-
资助金额:$23.52万
-
财政年份:2013
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes for Protein Kinases
-
批准号:8072237
-
项目类别:
-
资助金额:$10.0万
-
财政年份:2010
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes For Protein Kinases
-
批准号:8577462
-
项目类别:
-
资助金额:$30.36万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes For Protein Kinases
-
批准号:8731913
-
项目类别:
-
资助金额:$30.36万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes For Protein Kinases
-
批准号:10089456
-
项目类别:
-
资助金额:$31.78万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes for Protein Kinases
-
批准号:7566645
-
项目类别:
-
资助金额:$28.72万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes for Protein Kinases
-
批准号:8325372
-
项目类别:
-
资助金额:$27.47万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
New Molecular Probes for Protein Kinases
-
批准号:7924157
-
项目类别:
-
资助金额:$28.12万
-
财政年份:2008
-
负责人:Dustin J Maly
-
依托单位:
海外基金