Sphingolipid signaling in age-associated vascular pathology
Sphingolipid signaling in age-associated vascular pathology
批准号:
10506516
负责人:
Timothy Tun Hla
金额:
$50.55万
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:
2022-09-01 至 2027-05-31
关键词:
AddressAgeAgingAirAlveolarAortaArchitectureAtherosclerosisAttenuatedBlindnessBlood VesselsCell LineCell physiologyCellsChromatinChronicClinicalDataDefectDementiaDiseaseEndothelial CellsEventExhibitsFrequenciesFunctional disorderGasesGene ExpressionGene Expression ProfileGeneticGenetic ModelsGenetic TranscriptionHigh Density LipoproteinsHost DefenseHumanInflammationInflammatoryInjuryKnock-inKnowledgeLaboratoriesLeadLungModelingMolecular ChaperonesMorbidity - disease rateMosaicismMusNerve DegenerationNeuraxisOrganOutcomePathologicPathologic ProcessesPathologyPathway interactionsPatternPhenotypePhysiologicalPopulationProstaglandinsPulmonary FibrosisResistanceRetinaSLC2A1 geneSignal PathwaySignal TransductionSiteSphingolipidsSphingosine-1-Phosphate ReceptorStressSupporting CellTFRC geneTestingTherapeuticThrombosisTransgenic OrganismsVascular DiseasesVascular Endothelial CellVascular SystemVesicleViralVirus DiseasesWNT Signaling Pathwayage relatedagedaging populationastrogliosisbasebeta-arrestincombatdesignfrailtygenetic signaturehuman old age (65+)influenza infectioninsightlipid mediatormortalitymouse geneticsmouse modelmutantnovel therapeutic interventionprogramspulmonary functionresiliencesenescencesingle-cell RNA sequencingsphingosine 1-phosphatetranscriptomevascular abnormality
中文摘要
点击翻译按钮获取中文摘要
英文摘要
SUMMARY
Age-related decline in vascular function is a key factor in decreased organ function,
vitality, resistance to stress and increased morbidity/ mortality. Our laboratory has made
long-standing contributions about how lipid mediators (sphingolipids and prostanoids) enhance
vascular endothelial cells (EC) function and resilience to pathological processes. Our recent
data suggest that age-dependent decline in EC protective sphingosine 1-phosphate (S1P)
signaling contributes to EC dysfunction and pathology of various organs. Specifically, circulatory
HDL-bound S1P signaling via EC S1P receptor-1 (S1PR1) is a key mechanism that enhances
EC resilience and that therapeutic strategies designed to counter its age-dependent decline was
efficacious in reducing organ pathology. This premise is further supported by unbiased studies
in humans which show age-dependent decrease in ApoM, the S1P chaperone on HDL. We
hypothesize that aging compromises vasculoprotective S1P pathway which enhances EC
resilience, thus contributing to rapid decline in organ function. The corollary of the hypothesis is
that mechanism-based therapeutic enhancement of EC S1PR1 pathway will decrease the rate
of decline of organ-specific EC. To understand organ-specific vascular aging mechanisms, we
profiled the transcriptome and chromatin regulatory sites globally from freshly isolated EC from
normal mouse aorta, lung and retina. EC defects in these organs lead to atherosclerosis,
reduced resistance to viral infections and vascular pathology in central nervous system (CNS),
respectively. First, we will characterize an aging-induced aortic endothelial cell-2 (AEC2)
population which has attenuated S1PR1 signal while exhibiting inflammatory and fibrotic gene
signature. We will define age-associated chromatin regulators of AEC2 cells and assess the
ability of S1PR1/ Gi-biased signals to counteract this pathological EC phenotype change in aged
mice. Second, we will test the hypothesis that EC S1PR1 signaling in lung EC (LEC) supports
resilience against viral infections. Mechanisms by which aging attenuates LEC S1PR1 signaling
will be elucidated. Therapeutic strategies that mimic HDL-S1P that suppress pathological
phenotypes will be tested. Third, using the retinal EC (REC) as a model of the CNS
vasculature, we will examine whether S1PR1 signal can counter age-related barrier breach,
transporter gene expression and astrogliosis either alone or in combination with the Wnt
signaling activators. These studies are anticipated to lead to new insights by which lipid
mediators contribute to vascular dysfunction and disease during aging, which could ultimately
lead to novel therapeutic strategies to combat age-related organ dysfunction and decline.
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批准号:8150054
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资助金额:$11.8万
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依托单位:
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