Targeting chitin in fibrotic lung disease
靶向几丁质治疗纤维化肺病
基本信息
- 批准号:10579959
- 负责人:
- 金额:$ 42.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAllelesAnimal ModelApoptosisArchitectureBiologicalBiological AssayCell physiologyCellsChitinChitinaseChronicChronic lung diseaseComplexCoupledCouplingDNA DamageDNA Sequence AlterationDataDepositionDevelopmentDiagnosisDiagnosticDiseaseDisease ProgressionDoseDustEnvironmentEnvironmental Risk FactorEnzymesEpithelial CellsEpitheliumEtiologyExtracellular MatrixFibrosisFunctional disorderGeneticGenetic Predisposition to DiseaseHumanImmuneImpairmentIndividualInflammatoryInterstitial Lung DiseasesKnock-outLinkLungLung TransplantationMediatingMetalsModelingMolecularMouse StrainsMusMutationOrgan failurePathogenesisPathway interactionsPatientsPolysaccharidesPopulationProcessProteinsPulmonary ChallengePulmonary FibrosisReactive Oxygen SpeciesReporterRoleSilicon DioxideSourceSystemTelomeraseTestingTherapeuticTissuesTransgenic OrganismsType II Epithelial Receptor CellVariantVirus DiseasesWild Type Mouseacidic mammalian chitinaseage relatedagedalveolar epitheliumcaspase 14cigarette smokedesigneffective therapyendoplasmic reticulum stressenzyme activityenzyme replacement therapyepithelial injuryexperimental studyfibrotic lungfibrotic lung diseasegain of functionidiopathic pulmonary fibrosisimprovedin vivoin vivo evaluationinnovationinterstitialloss of functionlung developmentlung preservationmortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticsorgan injuryparticlepreventpulmonary functionrapid testingrepairedresponseresponse to injurysenescencetherapeutic candidate
项目摘要
ABSTRACT
Healthy lung function is maintained by epithelial cells that comprise the barrier between environmental
constituents and host tissues. These cells become dysregulated in chronic inflammatory and fibrotic lung
disease, reflecting both genetic and environmental contributions. We have identified a novel association
between an abundant environmental polysaccharide and the progression of lung fibrosis. This polysaccharide,
chitin, accumulates abnormally in the airways of humans with idiopathic pulmonary fibrosis (IPF), an
irreversible, fatal interstitial lung disease that is not completely understood. IPF has been linked to alveolar
epithelial cell dysfunction and unknown environmental factors. Chitin is normally degraded by acidic
mammalian chitinase (AMCase), a chitinolytic enzyme conserved in mice and humans that is secreted by lung
epithelial cells to mediate chitin clearance from the airways. Our results indicate that AMCase is produced by
epithelial cells that may be directly involved in the pathogenesis of lung fibrosis. Environmentally-derived chitin
spontaneously accumulates in the airways of mice lacking AMCase or bearing IPF-associated genetic
mutations, coincident with the development of age-related lung fibrosis in both strains. Additionally, whereas
wild-type mice resolve fibrosis after acute epithelial injury, AMCase-deficient mice progress to severe interstitial
lung fibrosis associated with increased mortality, resembling key aspects of human fibrotic lung disease that
have been difficult to recapitulate in animal models. Together, these data suggest that the routine process of
degrading insoluble chitin particles in the airways is dysregulated in lung fibrosis and may be a relevant
environmental driver of disease. We have generated several genetic knockout, transgenic, and reporter mice
that enable the tracking and functional assessment of relevant lung epithelial cell populations. These different
mouse strains will be used to dissect the contributions of the mammalian chitinolytic system and associated
epithelial cells to the development of lung fibrosis. We will characterize the molecular mechanisms of chitin
degradation using novel assays incorporating common human and mouse enzyme variants on complex
substrates. These assays are coupled with in vivo approaches that will allow for rapid testing of therapeutic
candidates that can target natural substrates in a lung fibrosis setting. Thus, in this project, we propose
coupling therapeutic chitinase development with the study of how chitin drives fibrotic lung disease in three
aims: 1. To determine the contribution of environmental chitin to lung fibrosis. 2. To define the cellular and
molecular basis for chitinase activity in fibrotic disease. 3. To characterize the mechanisms of chitin
degradation mediated by human chitinases and test novel therapeutic approaches in vivo. Understanding
ways to efficiently target and degrade chitin in the context of fibrotic lung disease may advance new therapies
for a group of related diseases that currently lacks effective treatments.
抽象的
健康的肺功能由上皮细胞维持,上皮细胞构成环境之间的屏障
成分和宿主组织。这些细胞在慢性炎症和纤维化肺中变得失调
疾病,反映了遗传和环境的贡献。我们发现了一个新的关联
丰富的环境多糖与肺纤维化进展之间的关系。这种多糖,
几丁质在患有特发性肺纤维化(IPF)的人类呼吸道中异常积累,
不可逆的致命性间质性肺疾病尚未完全了解。 IPF 与肺泡有关
上皮细胞功能障碍和未知的环境因素。甲壳素通常会被酸性物质降解
哺乳动物几丁质酶(AMCase),一种在小鼠和人类中保守的几丁质分解酶,由肺分泌
上皮细胞介导几丁质从气道中的清除。我们的结果表明 AMCase 是由
上皮细胞可能直接参与肺纤维化的发病机制。环境来源的甲壳素
缺乏 AMCase 或携带 IPF 相关基因的小鼠气道中自发积聚
突变,与两种菌株中与年龄相关的肺纤维化的发展相一致。此外,鉴于
野生型小鼠在急性上皮损伤后解决了纤维化,AMCase 缺陷型小鼠进展为严重的间质性纤维化
肺纤维化与死亡率增加相关,类似于人类纤维化肺病的关键方面
很难在动物模型中重现。总之,这些数据表明,常规过程
气道中不溶性几丁质颗粒的降解在肺纤维化中失调,可能与肺纤维化有关
疾病的环境驱动因素。我们已经培育了几种基因敲除小鼠、转基因小鼠和报告小鼠
能够对相关肺上皮细胞群进行跟踪和功能评估。这些不同的
小鼠品系将用于剖析哺乳动物几丁质分解系统和相关的贡献
上皮细胞参与肺纤维化的发展。我们将表征甲壳素的分子机制
使用结合常见人类和小鼠酶变体的新型测定法进行降解
基材。这些测定与体内方法相结合,可以快速测试治疗效果
可以针对肺纤维化环境中的天然基质的候选者。因此,在这个项目中,我们建议
将治疗性几丁质酶的开发与几丁质如何驱动三种肺纤维化疾病的研究相结合
目的: 1. 确定环境几丁质对肺纤维化的影响。 2. 定义蜂窝和
纤维化疾病中几丁质酶活性的分子基础。 3. 表征甲壳素的作用机制
由人类几丁质酶介导的降解并在体内测试新的治疗方法。理解
在纤维化肺病的背景下有效靶向和降解几丁质的方法可能会推动新疗法的发展
针对目前缺乏有效治疗方法的一组相关疾病。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Finding a Niche: Tissue Immunity and Innate Lymphoid Cells.
寻找利基市场:组织免疫和先天淋巴细胞。
- DOI:10.1007/978-981-16-8387-9_5
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Jung,Haerin;Kim,Do-Hyun;Wang,Yilin;VanDyken,StevenJ
- 通讯作者:VanDyken,StevenJ
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{{ truncateString('Steven Van Dyken', 18)}}的其他基金
Chitin and chitinases in SARS-CoV-2 infection
SARS-CoV-2 感染中的几丁质和几丁质酶
- 批准号:
10742004 - 财政年份:2023
- 资助金额:
$ 42.18万 - 项目类别:
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