Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
基本信息
- 批准号:10360504
- 负责人:
- 金额:$ 46.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:ArthritisBiologicalBiological ProcessCCL2 geneCellsClinical TrialsComplexCoupledCuesDataDiabetic NephropathyDiseaseEndothelial CellsEtiologyExtracellular MatrixFeedbackG-Protein-Coupled ReceptorsGTP-Binding ProteinsGene SilencingInflammatoryInflammatory ResponseInterventionLigandsLiteratureLocationLysosomesMalignant neoplasm of pancreasMass Spectrum AnalysisMediatingMethodsMigration AssayModelingMutationNerve DegenerationNetwork-basedNeurodegenerative DisordersOutcomePathway interactionsPharmaceutical PreparationsPharmacologyPhosphorylationPhysiologicalPlasmaPreparationPropertyProteinsReactionRoleSignal PathwaySignal TransductionStimulusSystemTestingTherapeuticTimeTissuesTransducersTraumatic Brain InjuryValidationWorkantagonistbasecell motilitycell typechemokinechemokine receptorclinical efficacycohesioncomputer frameworkdesensitizationdirectional cellexperimental studyextracellularfatty liver diseasefluorescence imagingfollow-upin silicomigrationmonocytemonocyte chemoattractant protein 1 receptornetwork modelsnon-alcoholic fatty liver diseasenovelpodocytepreclinical studyreceptorrecruitresponsespatiotemporaltherapeutic developmenttherapeutic targettrafficking
项目摘要
Monocyte migration into tissues, guided by inflammatory chemokine CCL2 and its G protein-coupled receptor
CCR2, is key to both normal physiological responses and many diseases including neurodegenerative disease,
traumatic brain injury, arthritis, diabetic nephropathy and non-alcoholic fatty liver disease. Moreover, CCR2 is
currently the target of ongoing clinical trials for diabetic nephropathy and pancreatic cancer. Given the
therapeutic significance of CCR2, it is surprising that its role in monocyte function is so poorly understood. In
particular, while CCR2 is well-recognized to promote cell movement, what is largely unappreciated, is that it has
a second, equally important function, whereby it scavenges chemokines from the extracellular medium by
internalizing and trafficking chemokine to lysosomes for degradation. Scavenging may enable receptor-
expressing cells to move along gradients of increasing chemokine concentration without desensitizing; it may
also modulate the responsiveness of receptors on different cells by altering the availability of specific
chemokines, thereby regulating whether and what type of cells migrate. We hypothesize that it is, in fact, the
cohesive integration of these two functions (cell movement and scavenging) that enables CCR2 to effectively
control directional cell migration in different biological contexts. Moreover, we hypothesize that external cues
involving ligand concentration and interactions with extracellular matrix components define a switch between a
scenario where the receptor rapidly desensitizes and one where it remains responsive, continues to migrate,
and efficiently scavenges chemokine. The objective of this proposal is to achieve a comprehensive and predictive
systems-based understanding of the signaling and trafficking mechanisms that regulate CCR2 migration and
scavenging functions. Here we propose three Aims: (i) We will delineate the roles of key transducers of CCR2-
mediated migration and scavenging by combining pharmacological inhibition and gene silencing with cell
based assays of migration and scavenging and fluorescence imaging of receptor trafficking. We will also further
define the mechanisms that regulate the switch from receptors being desensitized upon activation to maintaining
responsiveness and becoming efficient scavengers; (ii) We will discover and characterize novel proteins that
regulate CCR2 migration and scavenging using unbiased Mass Spectrometry based approaches coupled with
orthogonal methods of analysis and Boolean network modeling to prioritize key regulators for validation as in
Aim 1; (iii) We will develop predictive in silico network-based models of CCR2 signaling and trafficking
using Boolean reaction-contingency networks initially informed by literature with refinement from systematic data
collected in Aims 1 and 2. The expected outcome of this proposal is predictive and spatiotemporally-resolved
interactome and signaling network of CCR2 that reveals currently unknown functional and regulatory
mechanisms of monocyte migration and scavenging.
炎症趋化因子CCL 2及其G蛋白偶联受体介导的单核细胞向组织迁移
CCR 2是正常生理反应和许多疾病包括神经退行性疾病的关键,
创伤性脑损伤、关节炎、糖尿病肾病和非酒精性脂肪肝。此外,CCR 2是
目前正在进行的糖尿病肾病和胰腺癌临床试验的目标。鉴于
尽管CCR 2具有显著的治疗意义,但令人惊讶的是,其在单核细胞功能中的作用知之甚少。在
特别是,虽然CCR 2被公认为促进细胞运动,但很大程度上未被认识到的是,它具有
第二个同样重要的功能,它从细胞外介质中清除趋化因子,
内化并运输趋化因子至溶酶体以进行降解。清除可能使受体-
表达细胞以使其沿着趋化因子浓度增加的梯度移动而不脱敏;它可以
还通过改变特异性受体的可用性来调节不同细胞上受体的反应性。
趋化因子,从而调节细胞是否迁移以及迁移类型。我们假设,事实上,
这两种功能(细胞运动和清除)的内聚整合使CCR 2能够有效地
在不同的生物学背景下控制定向细胞迁移。此外,我们假设外部线索
涉及配体浓度和与细胞外基质成分的相互作用,
受体迅速脱敏的情况和它保持响应的情况,继续迁移,
并有效清除趋化因子。本建议的目的是实现一个全面的和预测性的
基于系统的理解调节CCR 2迁移的信号传导和贩运机制,
清除功能。在这里,我们提出了三个目标:(i)我们将描绘CCR 2的关键换能器的作用,
通过结合药理学抑制和基因沉默与细胞介导的迁移和清除
基于迁移和清除的测定以及受体运输的荧光成像。我们还将进一步
定义调节受体从激活后脱敏到维持
反应和成为有效的清道夫;(ii)我们将发现和表征新的蛋白质,
使用基于无偏质谱法的方法调节CCR 2迁移和清除,
正交分析方法和布尔网络建模,以确定验证的关键调节器的优先顺序,如
目标1;(iii)我们将开发基于计算机网络的CCR 2信号传导和贩运预测模型
使用布尔反应-应急网络,最初由文献提供信息,并从系统数据中进行改进
在目标1和2中收集。该提案的预期结果是预测性的和时空解决的
CCR 2的相互作用组和信号网络,揭示了目前未知的功能和调节
单核细胞迁移和清除机制。
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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Tracy M Handel其他文献
Tracy M Handel的其他文献
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{{ truncateString('Tracy M Handel', 18)}}的其他基金
It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12
这是一场拉锯战:CXCR4 和 ACKR3 对淋巴细胞趋化剂 CXCL12 反应的结构、后果和抑制
- 批准号:
10393668 - 财政年份:2021
- 资助金额:
$ 46.5万 - 项目类别:
It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12
这是一场拉锯战:CXCR4 和 ACKR3 对淋巴细胞趋化剂 CXCL12 反应的结构、后果和抑制
- 批准号:
10597645 - 财政年份:2021
- 资助金额:
$ 46.5万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10559615 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10727691 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10627751 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10488001 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10397636 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
9917599 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10162570 - 财政年份:2020
- 资助金额:
$ 46.5万 - 项目类别:
Insights into Activation Mechanisms of G Protein-Coupled and Atypical β-Arrestin-Coupled Chemokine Receptors
深入了解 G 蛋白偶联和非典型 β-抑制蛋白偶联趋化因子受体的激活机制
- 批准号:
9899267 - 财政年份:2019
- 资助金额:
$ 46.5万 - 项目类别:
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