Mechanisms of exacerbation of COVID-19 pathogenesis in mice expressing human ACE2 by polycyclic aromatic hydrocarbons (PAHs), and its protection by inhibition of soluble epoxide hydrolase (sEH)
多环芳烃 (PAH) 表达人 ACE2 的小鼠中 COVID-19 发病机制恶化,以及通过抑制可溶性环氧化物水解酶 (sEH) 对其进行保护
基本信息
- 批准号:10337295
- 负责人:
- 金额:$ 20.06万
- 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:2021-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVACE2AcidsAcute Lung InjuryAcute Respiratory Distress SyndromeAdultAgeAirAnti-Inflammatory AgentsAromatic Polycyclic HydrocarbonsAttenuatedAutopsyBenzo(a)pyreneBody Weight decreasedCCL2 geneCOVID-19COVID-19 pathogenesisCOVID-19 treatmentCYP11A1 geneCell SeparationCellsChemosensitizationClinical TrialsDataDiesel ExhaustDisease OutbreaksEicosanoidsEicosatrienoic AcidEnvironmental PollutantsEnzyme-Linked Immunosorbent AssayEpoxide hydrolaseExperimental DesignsExposure toFemaleFunctional disorderFutureGene Expression ProfilingGenesHistologyHumanHydration statusHydroxyeicosatetraenoic AcidsHyperoxiaIL8 geneImmuneIndividualInfectionInflammationInflammatoryInjuryInterleukin-1Interleukin-1 betaInterleukin-6K-18 conjugateLifeLungLung diseasesMeasuresMediatingModelingMolecularMultiple Organ FailureMusNamesOxidative StressOxygenPathologyPathway interactionsPatientsPhasePopulationPulmonary InflammationReceptor CellRiskRoleSARS coronavirusSARS-CoV-2 exposureSARS-CoV-2 infectionSevere Acute Respiratory SyndromeSmokerStromal CellsSymptomsSyndromeTNF geneTestingTransgenic MiceTransgenic OrganismsUreaViralVirusVirus DiseasesWestern BlottingWild Type Mousebetacoronaviruscigarette smokecigarette smokingcytokinecytokine release syndromedrinking waterenvironmental chemicalexperimental studyinhibitorlung injurymacrophagemalemolecular phenotypeneutrophilnon-smokernovelpollutantpreventreceptorrecruitrespiratorysevere COVID-19single-cell RNA sequencing
项目摘要
Project Summary
Severe coronavirus disease (COVID-19) is caused by a novel Beta-coronavirus, now named
SARS-CoV-2. COVID-19 is characterized by unresolved systemic hyperinflammation associated
with a life-threatening “cytokine storm syndrome”, leading to multi-organ failure dysfunction in
some patients. Recent studies have shown that cigarette smoking and other environmental
pollutants exacerbate respiratory illness in COVID-19 infected individuals, but the mechanisms
responsible for the potentiation of lung disease is not known. Models of lung damage due to
environmental chemicals (e.g., cigarette smoking) include the use of polycyclic aromatic
hydrocarbons (PAH), especially benzo[a]pyrene (BP), which are present in cigarette smoke,
charbroiled steaks, diesel exhausts etc. In these models, additional hyperoxic exposure leads to
exacerbation of ARDS-like symptoms. Current data suggests that using a soluble epoxide
hydrolase inhibitor (sEHI) protects against lung injury related to ARDS, as they prevent hydration
of anti-inflammatory eicosanoids [e.g., epoxy eicasotrienoic acids (EETs). The central
hypothesis proposed in this application is that BP would exacerbate lung
injury/inflammation during SARS-CoV-2 infection, and subsequent hyperoxia exposure,
and that treatment of these mice with sEHI would confer protection against lung injury.
Gene expression profiling using single cell RNA-Seq and FACS approaches will be done to
determine the molecular pathways of lung injury and inflammation mediated by BP/SARS-CoV-
2/hyperoxia. We propose the following specific aims: 1. To test the hypothesis that transgenic
K18-hACE2 mice that are treated with BP prior to infection with SARS-CoV-2 will be more
susceptible to lung injury than those that are mock treated prior to infection. We will also test the
hypothesis that treatment with the sEHI TPPU will confer protection against lung injury/ARDS in
the BP/SARS-COV-2/-exposed mice. Gene expression profiling using single cell RNA-seq will be
performed to determine the role of specific lung cells in lung injury mediated by BP/SARS-CoV-2
and its protection by sEHI. 2. To test the hypothesis that exposure of BP/SARS-CoV-2 treated
mice to hyperoxia will lead to further exacerbation of lung injury compared to those maintained in
room air, and that these mice will display lesser injury if they were exposed to sEHI treatment
during the hyperoxia phase. The proposed studies will unravel molecular mechanisms of lung
injury mediated by SARS-CoV-2/hyperoxia, and its potentiation by environmental PAHs.
Furthermore, if our sEHI studies aimed to protect mice against COVID-19 pathogenesis, it will be
a big step towards future clinical trials on the use of sEHs for treatment of COVID019 in humans.
项目总结
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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{{ truncateString('BHAGAVATULA MOORTHY', 18)}}的其他基金
Mechanisms of exacerbation of COVID-19 pathogenesis in mice expressing human ACE2 by polycyclic aromatic hydrocarbons (PAHs), and its protection by inhibition of soluble epoxide hydrolase (sEH)
多环芳烃 (PAH) 表达人 ACE2 的小鼠中 COVID-19 发病机制恶化,以及通过抑制可溶性环氧化物水解酶 (sEH) 对其进行保护
- 批准号:
10156460 - 财政年份:2021
- 资助金额:
$ 20.06万 - 项目类别:
POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION
多环芳烃:超灵敏检测、生命早期暴露-临床结果(早产、慢性肺病和神经认知缺陷)、预防和补救
- 批准号:
10401127 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
Proj3:Role of cytochrome P450 (CYP)1A/1B1 enzymes in the potentiation of neonatal lung injury in newbron mice exposed prenatally to PHs, and increased risk of premature infants to chronic lung disease
Proj3:细胞色素 P450 (CYP)1A/1B1 酶在产前暴露于 PH 的新生小鼠中增强新生儿肺损伤中的作用,并增加早产儿患慢性肺病的风险
- 批准号:
10116394 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
Proj3:Role of cytochrome P450 (CYP)1A/1B1 enzymes in the potentiation of neonatal lung injury in newbron mice exposed prenatally to PHs, and increased risk of premature infants to chronic lung disease
Proj3:细胞色素 P450 (CYP)1A/1B1 酶在产前暴露于 PH 的新生小鼠中增强新生儿肺损伤中的作用,并增加早产儿患慢性肺病的风险
- 批准号:
10559705 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION
多环芳烃:超灵敏检测、生命早期暴露-临床结果(早产、慢性肺病和神经认知缺陷)、预防和补救
- 批准号:
10382017 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION
多环芳烃:超灵敏检测、生命早期暴露-临床结果(早产、慢性肺病和神经认知缺陷)、预防和补救
- 批准号:
10559666 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
Core A: Administrative and Research Translation Core (ARTC)
核心 A:行政和研究翻译核心 (ARTC)
- 批准号:
10116385 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
Core A: Administrative and Research Translation Core (ARTC)
核心 A:行政和研究翻译核心 (ARTC)
- 批准号:
10559668 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION
多环芳烃:超灵敏检测、生命早期暴露-临床结果(早产、慢性肺病和神经认知缺陷)、预防和补救
- 批准号:
10116383 - 财政年份:2020
- 资助金额:
$ 20.06万 - 项目类别:
Mechanistic role of P4501 enzymes in the prevention of PAH carcinogenesis by omega 3 fatty acids
P4501 酶在 omega 3 脂肪酸预防 PAH 致癌中的机制作用
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10163846 - 财政年份:2018
- 资助金额:
$ 20.06万 - 项目类别:
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