Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
基本信息
- 批准号:10470338
- 负责人:
- 金额:$ 48.65万
- 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:2020-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAirway FibrosisAmphotericin BAnionsAnti-Bacterial AgentsAreaBicarbonatesCell physiologyCellsCellular biologyChloridesComplementCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDefectDevelopmentDiseaseDisease ProgressionDuct (organ) structureEctopic ExpressionEpithelial CellsFerretsGeneticGenetic EngineeringGlandGoalsHalf-LifeHumanIn VitroInflammationIon ChannelKnowledgeLaboratoriesLiquid substanceLungMediatingMessenger RNAModelingMolecularMovementMucociliary ClearanceMusNON MouseNatural ImmunityPathogenesisPhenotypeProcessPropertyPulmonary Cystic FibrosisRegulationReporterResearchSurfaceTechnologyTestingTransgenic Organismsabsorptionairway epitheliumairway surface liquidcell typecellular targetingcystic fibrosis airwaydefined contributiondetection limitdisease phenotypeepithelial Na+ channelgain of functiongene complementationgene replacementgene therapygenetic approachin vivoloss of functionoverexpressionporcine modelpreventpulmonary functionrestorationsingle-cell RNA sequencingsynergism
项目摘要
Project-3 Summary
Complexities in CFTR-expressing epithelial cells of the conducting human and mouse airway were recently
revealed by single-cell RNA sequencing (scRNAseq). These studies identified the ionocyte, an infrequent cell
type that expresses the majority of CFTR in the proximal airway and submucosal gland ducts. They also
showed that the repertoire of ion channels in the ionocyte is uniquely suited to potentially regulate airway pH.
However, whether only ionocytes contribute to innate immunity and clearance in the airways remains to be
determined; it is possible that other airway cell types, such as ciliated cells, express CFTR at levels that are
below the detection limits of scRNAseq yet are functionally important in the pathogenesis of CF lung disease.
Deeper knowledge of CFTR cellular physiology in the airway will greatly enhance our understanding of CF
pathogenesis, while also informing the cellular targets for gene therapy of CF lung disease. The proposed
project will focus on understanding the cellular functions of CFTR in ionocytes and ciliated cells, and whether
CFTR expression in each of these cell types is required or sufficient to prevent CF lung disease. Our
hypotheses will be tested in genetic ferret models, a species that more accurately reflects human CF lung
disease than mice. These studies are possible because of the creation of several new genetic ferret models
that can conditionally (in specific cell types) inactivate CFTR expression on a wild-type (WT) background or
reactivate CFTR expression on a CF background. Both of these strategies use CreERT2 technologies and
enable lineage tracing of the targeted cells in vivo using a fluorescent Cre-reporter. Additionally, we propose to
generate a new genetic ferret model in which CFTR is overexpressed specifically in ciliated cells, to test
whether high-level ectopic expression therein is sufficient to protect from CF lung disease. Key goals of this
project are to: 1) define the contributions of CFTR expression in ionocytes and ciliated cells to CF lung
pathogenesis, 2) determine the half-lives of ionocytes and ciliated cells in the CF and non-CF airway, and 3)
determine the extent to which CFTR expression in ionocytes and ciliated cells contributes to the regulation of
disease-relevant features of the airway surface liquid (ASL) (i.e. volume, antibacterial activity, chloride and
bicarbonate transport, and pH) and to mucociliary clearance. Each of these goals draws on the unique ability of
the Engelhardt laboratory to genetically engineer transgenic ferrets to temporally regulate CFTR expression in
specific cell types and to test these models for CF-relevant functional endpoints in vivo and in vitro. The
proposed study is the first to use state-of-art functional genetic approaches in a non-mouse species to tackle
difficult cell biology questions relating to CFTR function in the airway and CF lung pathogenesis. This research
is expected to significantly enhance the field's ability to develop effective genetic therapies for CF lung disease.
项目三总结
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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JOHN F ENGELHARDT其他文献
JOHN F ENGELHARDT的其他文献
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{{ truncateString('JOHN F ENGELHARDT', 18)}}的其他基金
Biology of Submucosal Gland Stem Cells in the Airway
气道粘膜下腺干细胞的生物学
- 批准号:
10516449 - 财政年份:2022
- 资助金额:
$ 48.65万 - 项目类别:
National Ferret Research and Resource Institute (NFRRI) at University of Iowa
爱荷华大学国家雪貂研究与资源研究所 (NFRRI)
- 批准号:
10596901 - 财政年份:2022
- 资助金额:
$ 48.65万 - 项目类别:
Biology of Submucosal Gland Stem Cells in the Airway
气道粘膜下腺干细胞的生物学
- 批准号:
10649543 - 财政年份:2022
- 资助金额:
$ 48.65万 - 项目类别:
Early Pathogenesis of Cystic Fibrosis Related Diabetes
囊性纤维化相关糖尿病的早期发病机制
- 批准号:
10599931 - 财政年份:2021
- 资助金额:
$ 48.65万 - 项目类别:
Early Pathogenesis of Cystic Fibrosis Related Diabetes
囊性纤维化相关糖尿病的早期发病机制
- 批准号:
10397094 - 财政年份:2021
- 资助金额:
$ 48.65万 - 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
- 批准号:
10677622 - 财政年份:2020
- 资助金额:
$ 48.65万 - 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
- 批准号:
10248531 - 财政年份:2020
- 资助金额:
$ 48.65万 - 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
- 批准号:
10024668 - 财政年份:2020
- 资助金额:
$ 48.65万 - 项目类别:
National Ferret Resource and Research Center on Lung Disease
国家雪貂资源与肺部疾病研究中心
- 批准号:
8751112 - 财政年份:2014
- 资助金额:
$ 48.65万 - 项目类别:
National Ferret Resource and Research Center on Lung Disease
国家雪貂资源与肺部疾病研究中心
- 批准号:
9283593 - 财政年份:2014
- 资助金额:
$ 48.65万 - 项目类别:
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