Role of lacrimal gland myoepithelial cells in dry eye disease
泪腺肌上皮细胞在干眼病中的作用
基本信息
- 批准号:10553199
- 负责人:
- 金额:$ 48.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acinar CellAcinus organ componentActinsAgeAnimal ModelAtrophicAutoimmuneCandidate Disease GeneCatabolismCell SeparationCell physiologyCellsChronicContractile ProteinsContractsCouplingDataDenervationDiseaseDown-RegulationDry Eye SyndromesDuctal Epithelial CellEfferent NeuronsG-Protein-Coupled ReceptorsGTP-Binding ProteinsGene ExpressionGenesGlandGoalsHealthHumanImpairmentIn VitroInflammationInflammatoryInterleukin-1Knock-outKnowledgeLacrimal gland structureLeadMAPK8 geneMMP2 geneMammary glandMediatingMetalloproteasesMicrofilamentsMolecularMusMuscleMuscle ProteinsMuscle denervation procedureMuscular AtrophyMyoepithelial cellN-terminalNeuropeptidesOutputOxytocinOxytocin ReceptorPathogenesisPathway interactionsPhosphotransferasesProcessProductionProteinsProteomicsRNAReceptor CellReceptor SignalingReportingRoleSecond Messenger SystemsSignal TransductionSignal Transduction PathwaySjogren&aposs SyndromeSmooth MuscleSmooth Muscle MyocytesSortingStressSystemTechniquesTissuesTranslatingUbiquitinaqueouscalponincell typecytokinemammarymilk productionmilk secretionmulticatalytic endopeptidase complexmuscular systemneuralneurotransmitter releasenew therapeutic targetnovelprotein expressionreceptorreceptor expressionresponsesextranscriptome sequencing
项目摘要
Chronic inflammation of the lacrimal gland (LG), as occurs in Sjögren’s syndrome, is the leading cause of aqueous-
deficient dry eye disease (DED). The mechanisms leading to insufficient LG secretion are still not completely understood.
The LG is composed of acinar, myoepithelial, and ductal cells, with acini and myoepithelial cells (MEC) forming the secretory units. MECs express several muscle proteins, such as alpha smooth muscle actin (SMA) and calponin, and are therefore able to contract. MECs are best studied in the mammary gland where their contraction is shown to be crucial for milk production and contraction is mainly controlled by the neuropeptide oxytocin. Despite their potential critical role in LG secretion, very little is known about MEC contraction in this tissue, nor is the impact of chronic inflammation of the LG on these cells. One of goals of the current proposal is to fill this gap in knowledge. Our preliminary studies show that murine and human LG MECs express the oxytocin receptor (OXTR) and contract in response to oxytocin stimulation. Furthermore, we show that MECs in chronically inflamed LG are atrophied, with down-regulation of contractile proteins SMA and calponin and the OXTR and MECs from these glands do not contract in response to oxytocin stimulation. We previously reported that interleukin-1 (IL-1) inhibits neurotransmitter release from LG efferent nerves leading to DED. We also reported activation of the stress activated c-Jun N-terminal kinase (JNK) and metalloproteinases 2 (MMP2) in chronically inflamed LGs and that inhibition of either pathway restored LG secretion and tears output in animal models of DED. Numerous studies showed that denervation of muscle tissues leads to tissue atrophy and degradation of muscle contractile proteins via the ubiquitin/proteasome pathways. Based on these findings, we hypothesize that in chronic DED, proinflammatory cytokines inhibit neurotransmitter release from LG efferent nerves creating a denervated-like tissue and that they trigger degradation of the OXTR and MEC myofilament proteins. This degradation translates into a loss of contractibility of MECs thus further exacerbating the effect of the loss of neural input on the secretory units of the LG. We further hypothesize that the JNK, MMP2, and ubiquitin/proteasome pathways mediate the effects of proinflammatory cytokines on MEC functions. We will use both in vitro (sorted MEC cells) as well as animal models of DED to investigate how proinflammatory cytokines interfere with oxytocin-induced contraction of LG MECs. We will use unbiased RNA-seq and quantitative global proteomics techniques to identify novel pathways that are altered in MECs in chronically inflamed LGs. At the completion of these studies, we will have established a role for the MEC, an important and yet understudied cell in the LG, and the oxytocin signaling system in the pathogenesis of aqueous-deficient DED and identified potential novel therapeutic targets.
泪腺(LG)的慢性炎症,如Sjögren综合征,是导致含水性流泪的主要原因
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of the adenylate cyclase/cyclic AMP pathway in oxytocin-induced lacrimal gland myoepithelial cells contraction.
腺苷酸环化酶/环AMP途径在催产素诱导的泪腺肌上皮细胞收缩中的作用。
- DOI:10.1016/j.exer.2023.109526
- 发表时间:2023
- 期刊:
- 影响因子:3.4
- 作者:Gárriz,Angela;Morokuma,Junji;Toribio,Danny;Zoukhri,Driss
- 通讯作者:Zoukhri,Driss
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DRISS ZOUKHRI其他文献
DRISS ZOUKHRI的其他文献
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{{ truncateString('DRISS ZOUKHRI', 18)}}的其他基金
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
7584767 - 财政年份:2009
- 资助金额:
$ 48.38万 - 项目类别:
STIMULUS/SECRETION COUPLING IN DISEASED LACRIMAL GLAND
患病泪腺中的刺激/分泌耦合
- 批准号:
6138222 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
6936505 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
8585380 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
STIMULUS/SECRETION COUPLING IN DISEASED LACRIMAL GLAND
患病泪腺中的刺激/分泌耦合
- 批准号:
6342671 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
6954754 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
6686982 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
Stimulus-Secretion Coupling in Diseased Lacrimal Gland
患病泪腺中的刺激-分泌耦合
- 批准号:
8721960 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
STIMULUS/SECRETION COUPLING IN DISEASED LACRIMAL GLAND
患病泪腺中的刺激/分泌耦合
- 批准号:
6489847 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别:
STIMULUS/SECRETION COUPLING IN DISEASED LACRIMAL GLAND
患病泪腺中的刺激/分泌耦合
- 批准号:
2739215 - 财政年份:1999
- 资助金额:
$ 48.38万 - 项目类别: