Regulation of Chemotactic Signaling
趋化信号的调节
基本信息
- 批准号:10798693
- 负责人:
- 金额:$ 1.34万
- 依托单位:
- 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:2019-06-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ArthritisAsthmaAtherosclerosisBackBiochemicalBiological AssayBiophysical ProcessCell LineCell membraneCellsChemicalsChemotactic FactorsChemotaxisCytoskeletonDiseaseEmbryonic DevelopmentEngineeringFluorescence Resonance Energy TransferImmune responseKnock-outLaboratoriesLigand BindingLogicMalignant NeoplasmsMedicalMicroscopyMonomeric GTP-Binding ProteinsMusNeoplasm MetastasisPIK3CG genePTEN genePathway interactionsPhosphoric Monoester HydrolasesPhosphotransferasesPhysiologicalPhysiological ProcessesProteinsRegulationScienceSignal PathwaySignal TransductionSystemTestingTherapeutic InterventionTranslatingXenograft Modelcell behaviorcell motilitychronic inflammatory diseasefMet-Leu-Phe receptorin vivointerestlive cell imagingmigrationmutantpolarized cellreceptorreconstitutionrhosingle moleculetherapeutic developmenttumortumorigenesiswound healing
项目摘要
Summary
Chemotactic cell migration underlies embryonic development, wound healing and immune responses.
Furthermore, aberrant chemotaxis leads to chronic inflammatory disease and tumor metastasis. My
laboratory has long been interested in signaling mechanisms that control cell behaviors in chemotaxis. In
a chemical gradient, cells polarize intracellular signaling and migrate toward chemoattractants. Ligand
binding to chemoattractant receptors selectively activates two kinases, TORC2 and PI3K, at the front of
cells. TORC2 and PI3K are the master kinases that induce cytoskeletal remodeling to extend
pseudopods and function immediately downstream of chemotactic receptors. Polarized activation of
these two kinases is essential for creating the leading edge of cells that migrate in a chemical
gradient. Despite the critical relevance to basic and medical science, an understanding of the spatial and
temporal regulation of TORC2 and PI3K remains incomplete. An overarching challenge is to decipher
how the TORC2 and PI3K signaling pathways are regulated at the front versus the back of cells in
a chemical gradient.
To explore mechanisms that regulate the TORC2 pathway, we will take advantage of our recently
developed biochemical systems. In these systems, chemoattractant-regulated activation and inhibition of
TORC2 are faithfully reconstituted with purified TORC2 and two small GTPases, Rho and Ras. These
new assays will identify the biochemical and biophysical mechanisms that create distinct chemotactic
signaling at the leading and trailing edges of migrating cells. The mechanistic principle that is determined
will be tested and translated in our cellular reconstitution systems using knockout cell lines expressing
WT and mutant TORC2 and its regulatory components. Using live-cell imaging with FRET microscopy
and single-molecule microscopy, we will place the signaling principle in a spatial and temporal context in
migrating cells. For the PI3K pathway, we will analyze proteins that control the localization of the PIP3
phosphatase PTEN to the plasma membrane at the back of cells. The rear localization of PTEN enables
PIP3 signaling activation at the leading edge and its inhibition at the trailing edge. We will also determine
the function of the identified mechanisms that control PTEN localization in tumorigenesis and metastasis
in mouse xenograft models expressing engineered PTEN molecules with altered localization. These
studies will elucidate the fundamental logics by which polarization of intracellular signaling is
established in cells during chemotactic migration and the physiological importance of this
signaling in vivo.
总结
趋化细胞迁移是胚胎发育、伤口愈合和免疫反应的基础。
此外,异常的趋化性导致慢性炎性疾病和肿瘤转移。我
长期以来,实验室一直对控制细胞趋化性行为的信号机制感兴趣。在
在化学梯度下,细胞抑制细胞内信号传导并向化学引诱物迁移。配体
与化学引诱物受体结合,选择性地激活两种激酶,TORC 2和PI3K,
细胞TORC2和PI3K是诱导细胞骨架重塑以延长细胞周期的主要激酶。
伪足并在趋化性受体的下游立即起作用。极化激活
这两种激酶对于创造细胞的前沿是必不可少的,
梯度离心尽管与基础科学和医学科学至关重要,但对空间和
TORC2和PI3K的时间调节仍然不完全。最大的挑战是破解
TORC2和PI3K信号通路是如何在细胞的前部与后部进行调节的,
化学梯度。
为了探索调节TORC 2通路的机制,我们将利用我们最近的研究成果,
发展了生化系统。在这些系统中,趋化因子调节的激活和抑制
TORC2用纯化的TORC2和两种小GTP酶Rho和Ras忠实地重构。这些
新的分析将确定产生不同趋化性的生物化学和生物物理机制,
在迁移细胞的前沿和后沿发出信号。机械原理决定了
将在我们的细胞重建系统中进行测试和翻译,
WT和突变型T0RC2及其调控组分。使用FRET显微镜的活细胞成像
和单分子显微镜,我们将把信号原理在空间和时间的背景下,
迁移细胞对于PI3K通路,我们将分析控制PIP3定位的蛋白质。
磷酸酶PTEN与细胞背面的质膜结合。PTEN的后部定位使得
PIP3信号在前沿激活,在后沿抑制。我们还将确定
已鉴定的控制PTEN定位的机制在肿瘤发生和转移中的作用
在表达具有改变的定位的工程化PTEN分子的小鼠异种移植模型中。这些
研究将阐明细胞内信号极化的基本逻辑,
在趋化性迁移过程中在细胞中建立,
体内信号传导
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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Miho Iijima其他文献
Miho Iijima的其他文献
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{{ truncateString('Miho Iijima', 18)}}的其他基金
Mechanism and Function of the Supercomplex KARATE in Insulin Signaling
超级复合物空手道在胰岛素信号传导中的机制和功能
- 批准号:
10444290 - 财政年份:2022
- 资助金额:
$ 1.34万 - 项目类别:
Mechanism and Function of the Supercomplex KARATE in Insulin Signaling
超级复合物空手道在胰岛素信号传导中的机制和功能
- 批准号:
10601093 - 财政年份:2022
- 资助金额:
$ 1.34万 - 项目类别:
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