Regulation of lipid metabolism in pulmonary Type 2 cells
肺2型细胞脂质代谢的调节
基本信息
- 批准号:10542430
- 负责人:
- 金额:$ 56.63万
- 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:2021-12-20 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:A549ABCA3 geneATP binding cassette transporter 1AcuteAddressAdipose tissueAdultAgonistAirAlveolarAnti-Inflammatory AgentsApicalAreaBleomycinBronchoalveolar LavageCell Culture SystemCell Differentiation processCell LineCell physiologyCellsCholesterolCholesterol EstersChronic DiseaseChronic Obstructive Pulmonary DiseaseChronic lung diseaseCoculture TechniquesCollagenComplexDataDefectDepositionDevelopmentDiagnosisDiseaseDown-RegulationElectron MicroscopyEnsureEpitheliumEventFibroblastsFibrosisFoundationsGene ExpressionGeneticGenetic ModelsGenetic TranscriptionHepaticHomeostasisHumanHydrolysisIn VitroInflammationInflammatoryInterleukin-1 betaInterventionKnock-outKnockout MiceKnowledgeLDL-Receptor Related Protein 1LecithinLipidsLipoprotein (a)Lipoprotein ReceptorLipoproteinsLiquid substanceLow Density Lipoprotein ReceptorLungLung diseasesMacrophageMeasuresMediatingMembraneMesenchymalMetabolicMetabolic PathwayMetabolismMolecularMorphologyMusOutcomePPAR gammaPathologyPathway AnalysisPathway interactionsPatientsPeptide HydrolasesPhenotypePhospholipidsProcessProteinsProteomicsPulmonary FibrosisPulmonary PathologyPulmonary SurfactantsPulmonologyRegulationResearchRespiratory physiologyRoleScienceSerpinsSignal TransductionSmooth Muscle MyocytesSourceSurface TensionSurfactant therapyTamoxifenTechniquesTestingTissuesTracerTransfectionVital capacityWork of Breathingadipocyte differentiationalveolar epitheliumalveolar lamellar bodycytokineextracellularidiopathic pulmonary fibrosisin vivoin vivo Modelinnovationintercellular communicationknock-downlipid biosynthesislipid mediatorlipid metabolismlipidomicsmRNA Expressionnovelnovel therapeutic interventionnovel therapeuticspreventpulmonary arterial hypertensionpulmonary functionreceptorresponserestorationsingle-cell RNA sequencingsmall hairpin RNAsurfactantsurfactant deficiencysurfactant productionsurfactant replacement therapysynthetic enzymetherapeutic targettranscriptome sequencingtranscriptomicsuptake
项目摘要
Surfactant insufficiency compromises pulmonary compliance and respiratory function in multiple pulmonary
pathologies. Our understanding of surfactant metabolism in adult pulmonary disease is very limited and this
restricts the potential for therapeutic targeting. In this project, we have generated a new genetic model of
surfactant insufficiency in adult disease by deleting the low-density lipoprotein receptor related protein 1 (LRP1)
specifically in surfactant producing type 2 cells (AEC2). LRP1 functions as lipoprotein receptor and extracellular
protease clearing receptor and it is associated with decreased respiratory function in patients with COPD and
pulmonary arterial hypertension. Studies in our generated cell line of LRP1 knockdown AEC2 (LRP1 KD) and
tamoxifen-inducible AEC2-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain
surfactant lipid secretion and intracellular lipid homeostasis to ensure optimal pulmonary compliance and
respiratory function. We hypothesize that LRP1 controls surfactant metabolism in AEC2 and we will study the
regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in
AEC2 and its regulation of the lipid source for surfactant synthesis in AEC2. In Aim 2 we will investigate the
epithelial to mesenchymal cross talk and the role of LRP1 in the progressive decline in lung function during
profibrotic challenges and molecular mechanisms responsible. We will attempt a new therapeutic approach to
stop the decline.
This proposal is innovative conceptually and technically. The role of AEC2 lipid metabolism during adult
pulmonary disease is unknown. LRP1 regulates many cellular functions through lipid metabolism in different
tissues and our study shows that it also regulates pulmonary function through surfactant lipid metabolism. In
addition, we use novel techniques that include inducible and cell-specific genetic knockout models in vivo lipid
tracing and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of
surfactant homeostasis in adult disease is very little understood. The significance of this research is further
underscored by the fact that surfactant lipid is altered in multiple pulmonary pathologies, including the most
prevalent ones.
表面活性物质不足损害肺顺应性和多肺呼吸功能
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Itsaso Garcia-Arcos其他文献
Itsaso Garcia-Arcos的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Itsaso Garcia-Arcos', 18)}}的其他基金
Regulation of lipid metabolism in pulmonary Type 2 cells
肺2型细胞脂质代谢的调节
- 批准号:
10367413 - 财政年份:2021
- 资助金额:
$ 56.63万 - 项目类别:
Regulation of lipid metabolism in pulmonary Type 2 cells
肺2型细胞脂质代谢的调节
- 批准号:
10002619 - 财政年份:2019
- 资助金额:
$ 56.63万 - 项目类别:
相似海外基金
Interstitial lung diseases (ILD) due to disturbed processing and function of the lipid transporter ABCA3 as a result of mutations in the ABCA3 gene
由于 ABCA3 基因突变,脂质转运蛋白 ABCA3 的加工和功能受到干扰,导致间质性肺疾病 (ILD)
- 批准号:
226491218 - 财政年份:2012
- 资助金额:
$ 56.63万 - 项目类别:
Research Grants