A Role of GAS6/Axl Signaling in the Development of Essential Hypertension
GAS6/Axl 信号传导在原发性高血压发展中的作用
基本信息
- 批准号:10447079
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAgeAmericanAngiotensin IIAnimal ModelAnti-Inflammatory AgentsAtherosclerosisAwardBlood PressureBlood VesselsBone Marrow TransplantationCD14 geneCardiovascular DiseasesCause of DeathCellsCellular Indexing of Transcriptomes and Epitopes by SequencingChronic Kidney FailureComb animal structureCytometryDataDendritic CellsDendritic cell activationDevelopmentDiagnosisDiseaseEndothelial CellsEndotheliumEpidemicEssential HypertensionExperimental ModelsFlow CytometryGeneticGenetic TechniquesGrowthGuidelinesHealthHeart failureHumanHypertensionIn VitroInflammasomeInflammationInflammatoryKidneyLeadLigandsLightMalignant NeoplasmsMechanicsMediatingMethodsMolecular GeneticsMorbidity - disease rateMusMyocardial InfarctionOrganOxidantsOxidative StressPathogenesisPharmacologyPhysiologicalPlayProductionPublishingRNAReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesRisk FactorsRoleSignal TransductionStimulusStretchingStrokeSurfaceT-Cell ProliferationTestingUnited StatesVeteransadductbaseblood pressure controlblood pressure reductioncell growthcombatcurative treatmentscytokineexposed human populationgenetic predictorshuman subjecthypertensiveimmune activationimprovedin vivomilitary veteranmonocytemortalitynew therapeutic targetnormotensivenovelnovel therapeuticspreventreceptorrenal damageresponsesialic acid binding Ig-like lectintherapy outcometranslational approach
项目摘要
PROJECT SUMMARY
Hypertension is the leading cause of morbidity and mortality from stroke, myocardial infarction, heart
failure, and chronic kidney disease amongst the United States Veterans. Despite the importance of
blood pressure control, the pathogenesis of essential hypertension remains poorly understood.
Recently, a new observation has shed light onto potential dendritic cells (DCs) that may be involved in
human hypertension. Using single-cell ribonucleic acid (RNA) sequencing, a new subset of DCs has
been described with surface expression of Axl and Siglec-6 in normal health subjects. They showed
that Axl+ Siglec-6+ DCs (AS DCs) can potently drive T cell proliferation and produce large amounts of
pro-inflammatory cytokines. Based on previously published studies and preliminary data, I propose that
hypertension leads to the release of endothelial-derived growth arrest specific 6 (GAS6) that activates
Axl on DCs leading to inflammation and its associated end organ damage. In Aim 1, I will test the
hypothesis that hypertensive stimuli lead to GAS6/Axl-dependent inflammasome activation mediated
by reactive oxygen species (ROS) in AS DCs. In this aim, I will expose human CD14+ monocytes to
GAS6 or hypertensive endothelial cell stretch and assess inflammasome activation, ROS production,
and the formation of the highly reactive Isolevuglandin (isoLG)-adducts by flow cytometry. I will also
examine the role of isoLGs on inflammasome activation by scavenging isoLGs using 2-
hydroxybenzilamine (2-HOBA) during exposure of human monocytes to hypertensive stimuli and
assess cytokine production by flow cytometry. Lastly, I will examine the response of AS DCs from
normotensive and hypertensive human subjects in an unbiased fashion by cellular indexing of
transcriptomes and epitopes by sequencing (CITE-seq). I predict that scavenging ROS and/or isoLGs
during exposure of GAS6 or endothelial cell stretch will prevent inflammasome activation and pro-
inflammatory cytokine release by AS DCs. In Aim 2, I will test the hypothesis that Axl-dependent
signaling in DCs promotes hypertension and its associated end-organ damage. I will use mice in which
I have deleted Axl specifically in DCs (Axlfl/fl and AxlCD11cCre). I will examine the in vivo role of Axl in DCs
during hypertension by radiotelemetry and flow cytometry. Next, I will investigate the deletion of Axl in
DCs on inflammasome activation and T cell proliferation in vitro by flow cytometry. I predict that genetic
deletion of Axl will prevent hypertension, DC activation, and its associated inflammation. In Aim 3, I will
test the hypothesis that GAS6 promotes DC activation, hypertension, and its associated inflammation
I will use mice that have genetic deletion for GAS6 (GAS6WT/WT and GAS6-/-). I will examine the in vivo
role of GAS6 by performing bone marrow transplantation studies and assess DC activation and
development of hypertension by flow cytometry and radiotelemetry. I will genetically delete GAS6 from
human endothelial cells and assess DC activation status and cytokine production by flow cytometry. I
predict that genetic deletion of GAS6 will prevent hypertension and activation of immune cells. These
studies will advance our understanding of the role DCs play in the development of human hypertension
and will provide new therapeutic directions for the treatment of human cardiovascular disease for United
States Veterans.
项目总结
项目成果
期刊论文数量(0)
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Justin Pieter Van Beusecum其他文献
Justin Pieter Van Beusecum的其他文献
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{{ truncateString('Justin Pieter Van Beusecum', 18)}}的其他基金
A Role of GAS6/Axl Signaling in the Development of Essential Hypertension
GAS6/Axl 信号传导在原发性高血压发展中的作用
- 批准号:
10664913 - 财政年份:2021
- 资助金额:
-- - 项目类别:
A Role of GAS6/Axl Signaling in the Development of Essential Hypertension
GAS6/Axl 信号传导在原发性高血压发展中的作用
- 批准号:
10255052 - 财政年份:2021
- 资助金额:
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A Role of GAS6/Axl Signaling in the Development of Essential Hypertension
GAS6/Axl 信号传导在原发性高血压发展中的作用
- 批准号:
10610110 - 财政年份:2021
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The role of salt and SGK1 on NADPH oxidase stabilization in dendritic cells in hypertension
盐和 SGK1 对高血压树突状细胞 NADPH 氧化酶稳定的作用
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9761140 - 财政年份:2019
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The role of salt and SGK1 on NADPH oxidase stabilization in dendritic cells in hypertension
盐和 SGK1 对高血压树突状细胞 NADPH 氧化酶稳定的作用
- 批准号:
10063425 - 财政年份:2019
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