Endothelial Cytoprotective Signaling by Activated Protein C/Protease-activated Receptor-1
激活蛋白 C/蛋白酶激活受体 1 的内皮细胞保护信号传导
基本信息
- 批准号:10816153
- 负责人:
- 金额:$ 4.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Anti-Inflammatory AgentsApoptosisApoptoticArr2ArrestinsBindingCRISPR/Cas technologyCaveolaeCell membraneCellsCytoprotectionEndothelial CellsEndotheliumExhibitsFutureG-Protein-Coupled ReceptorsGRK5 geneGoalsHumanInflammatory ResponseInjuryKnock-outMediatingMediatorMembrane MicrodomainsMorbidity - disease ratePAR-1 ReceptorPathway interactionsPhosphorylationPhysiologicalResearchSPHK1 enzymeSepsisSignal InductionSignal PathwaySignal TransductionSystemTestingTherapeuticThrombinTransducersVascular Diseasesactivated Protein Carrestin 2caveolin 1desensitizationendothelial dysfunctionimprovedinnovationmortalitynew therapeutic targetnovelreceptorresponsetherapeutic development
项目摘要
Summary/Abstract
There are currently limited treatment options for improving endothelial dysfunction in vascular diseases such as
sepsis, resulting in high morbidity and mortality. Endothelial dysfunction results in endothelial cell activation,
disruption of endothelial barrier function and sensitivity to apoptosis. The long-term goal of this proposal is to
delineate the pathways by which the endothelium can resist injury and disruption to facilitate the advancement
of new targets for therapeutic development. Activated protein C (APC) is a promising therapeutic and exhibits
multiple beneficial effects including stabilization of endothelial barriers and anti-apoptotic activities. Protease-
activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR), is the central mediator of APC cellular
signaling, which requires caveolin-1 (Cav1) and compartmentalization in caveolae. We discovered that APC-
activated PAR1 signals primarily through -arrestin-2 (-arr2) to promote endothelial barrier protection, and not
heterotrimeric G proteins like thrombin (Th)-activated PAR1. The overall objective of this proposal is to develop
a mechanistic understanding of how APC/PAR1 generates -arr2 transducer bias to promote endothelial
cytoprotection. We hypothesize that distinct GRK5 determinants and co-receptors facilitate APC/PAR1-induced
-arr2 transducer bias to promote endothelial cytoprotection through pathways enabled by Cav1
phosphorylation. We propose three specific aims. Aim 1: To delineate the mechanisms that enable GRK5 to
distinctly regulate APC- vs. Th-induced biased signaling. GRK5 is required for APC-stimulated signaling and
desensitization of Th-induced signaling. However, the mechanisms that enable distinct GRK5 functions are not
known. We will determine if distinct GRK5 functions are regulated by localization to discrete plasma membrane
microdomains such as caveolae using human cultured endothelial cells, a native system that permits the study
of endogenous PAR1 and GRK5 and HEK293 CRISPR/Cas9 knockout cells. Aim 2: To determine the
mechanisms by which APC vs. thrombin control -arrestin transducer bias. It is not known how -arrestin
transducer bias (signaling vs. desensitization) is induced by APC- vs. Th-activated PAR1 nor how APC/PAR1
promotes two distinct -arr2-mediated cytoprotective signaling pathways: dishevelled2 (Dvl2)-Rac1 controls
endothelial barrier protection whereas sphingosine kinase 1 (SphK1)-Akt regulates anti-apoptotic activities. We
will determine if distinct determinants of -arrestin and GPCR co-receptors control different -arr2 binding modes
and functions induced by APC vs. thrombin. Aim 3: To define the mechanisms by which APC/PAR1 regulates
Cav1 function to promote cytoprotection. APC/PAR1 stimulates Cav1 phosphorylation but how this modulates
Cav1 function and is integrated into the cytoprotective pathway is not known and will be determined. The
proposed research is innovative because it will test novel hypotheses to explain how GRK5, -arr2 and Cav1
drive APC/PAR1 endothelial cytoprotective responses in a physiologically relevant context and will help advance
the status of new targets as future therapeutics for the treatment of endothelial dysfunction.
摘要/文摘
项目成果
期刊论文数量(0)
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Joann Trejo其他文献
Joann Trejo的其他文献
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{{ truncateString('Joann Trejo', 18)}}的其他基金
Endothelial Cytoprotective Signaling by Activated Protein C/Protease-activated Receptor-1
激活蛋白 C/蛋白酶激活受体 1 的内皮细胞保护信号传导
- 批准号:
10594367 - 财政年份:2023
- 资助金额:
$ 4.98万 - 项目类别:
Cell Signaling by Protease-activated G Protein-coupled Receptors
蛋白酶激活的 G 蛋白偶联受体的细胞信号传导
- 批准号:
10371096 - 财政年份:2018
- 资助金额:
$ 4.98万 - 项目类别:
Cell signaling by G protein-coupled receptors
G 蛋白偶联受体的细胞信号传导
- 批准号:
10623554 - 财政年份:2018
- 资助金额:
$ 4.98万 - 项目类别:
Cell Signaling by Protease-activated G Protein-coupled Receptors
蛋白酶激活的 G 蛋白偶联受体的细胞信号传导
- 批准号:
9919120 - 财政年份:2018
- 资助金额:
$ 4.98万 - 项目类别:
Cell Signaling by Protease-activated G Protein-coupled Receptors
蛋白酶激活的 G 蛋白偶联受体的细胞信号传导
- 批准号:
9486492 - 财政年份:2018
- 资助金额:
$ 4.98万 - 项目类别:
Cell Signaling by Protease-activated G Protein-coupled Receptors
蛋白酶激活的 G 蛋白偶联受体的细胞信号传导
- 批准号:
9891860 - 财政年份:2018
- 资助金额:
$ 4.98万 - 项目类别:
2013 Molecular Pharmacology Gordon Research Conference and Gordon Research Semina
2013年分子药理学戈登研究会议暨戈登研究研讨会
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8520657 - 财政年份:2013
- 资助金额:
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