The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
基本信息
- 批准号:9764469
- 负责人:
- 金额:$ 16.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-16 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Adenine Nucleotide TranslocaseAnimal ModelApicalAwardBiologicalBiological ModelsBiologyCause of DeathCell DeathCell SurvivalCell membraneCell physiologyCell surfaceCellsCellular Metabolic ProcessChronic BronchitisChronic Obstructive Airway DiseaseChronic lung diseaseCiliaDataDevelopmentDictyosteliumDictyostelium discoideumDiseaseDisease ProgressionDisease modelEpithelialEpithelial CellsFoundationsFrequenciesFunctional disorderGene ExpressionGeneticGolgi ApparatusHealth Care CostsHomeostasisHumanHydration statusImmunoblottingImmunofluorescence ImmunologicImpairmentInjuryInner mitochondrial membraneKnockout MiceLungLung diseasesMembraneMentorsMetabolismMitochondriaMitochondrial Membrane ProteinModelingModificationMolecularMorbidity - disease rateMucociliary ClearanceMusObstructive Lung DiseasesPathogenesisPathway interactionsPatientsPeptide Signal SequencesPhenotypePhysiciansPlasmaPlayProcessProductionProtein IsoformsProteinsRegulationResearchRespirationRisk FactorsRoleSLC25A4 geneSLC25A5 geneSchemeScientistSmokeSolidSurfaceTestingTherapeuticTimeTissue imagingTissuesTrainingUnited States National Institutes of HealthWorkairway epitheliumairway surface liquidbody systemcareercareer developmentcellular imagingcigarette smokecigarette smoke-inducedcilium motilityeffective therapyexposure to cigarette smokefascinategain of functiongenetic selectionhuman modelmitochondrial metabolismmortalitymouse modelnew therapeutic targetnoveloverexpressionpreservationpreventprogramsprotective effectreconstitutionskillstherapeutic targettooltrafficking
项目摘要
PROJECT SUMMARY
The overall objectives of this NIH K08 Career Mentored Award are to identify and investigate new therapeutic
targets for epithelial injury due to cigarette smoke in chronic obstructive lung disease (COPD), and to facilitate
the development of essential skills that will allow the candidate to become an effective and independent
physician-scientist. The candidate and her mentors have constructed a rigorous training plan that will provide
the foundation for a strong and successful academic career. This proposal explores the core mechanisms of
how adenine nucleotide translocase (ANT) is localized to the plasma membrane of ciliated airway epithelium
and further how ANT is utilized for more advanced cellular functions, such as ciliary ATP regulation impacting
airway hydration and ciliary beating. COPD is the 3rd leading cause of death in the US with cigarette smoke
(CS) being the primary insult leading to disease. Despite ongoing mammalian research, no new biologic
targets have been identified, and current therapies have limited effect on disease progression or mortality. I
have leveraged the power of a genetically tractable model system, the amoebozoan Dictyostelium discoideum,
as a genetic selection discovery tool for lung biology. I identified human ANT (ANT1 and ANT2 present in lung)
as protective against CS-induced cell death in human bronchial epithelial cells. ANT is a mitochondrial
ADP/ATP transporter that plays an active role in mitochondrial metabolism and ATP homeostasis. While
exploring the localization of ANTs in human airway tissue, I made a fascinating observation that in addition to
mitochondrial localization, human ANT1 and ANT2 localize to the plasma membrane of motile cilia in human
airway and isolated primary airway cells (Normal Human Bronchial Epithelial cells, NHBE). GFP-tagged
adenoviral ANT1 and ANT2 also go to the ciliary membrane (and mitochondria) in primary NHBEs and ANT1
and ANT2 are present in isolated human ciliary axonemes by western analysis. In addition, ANT2 specifically
enhances airway surface hydration and preserves ciliary beat frequency in the context of CS. This early career
proposal answers the following questions: How does human ANT1 and ANT2 localize to the plasma
membrane of airway epithelium; how do plasma membrane versus mitochondrial ANTs regulate airway
metabolism, airway hydration and ciliary function in ciliated airway epithelium; and what is the impact of ANT2
loss and gain of function on airway dysfunction and COPD development through mouse models of disease
given its protective phenotype on airway epithelium. This will be accomplished using a combination of
molecular tools, ANT isoform genetic modification, cell and tissue imaging, real-time analysis of cellular
metabolism, assessment of airway hydration and ciliary function, and correlation with a mouse model of smoke
exposure. Ultimately, the role of ANT in lung disease has yet to be described and therapeutic manipulation of
its biology may allow us to drive cells to a healthier state. The core biology themes explored here will likely
have broad applicability and impact other lung diseases.
项目总结
NIH K08职业导师奖的总体目标是发现和研究新的治疗方法
慢性阻塞性肺疾病(COPD)吸烟致上皮损伤的靶点,并促进
发展基本技能,使应聘者成为一名有效和独立的
医生兼科学家。候选人和她的导师已经制定了一份严格的培训计划,将提供
这是一个强大而成功的学术生涯的基础。这项建议探讨了
腺核苷酸转位酶(ANT)如何定位于纤毛呼吸道上皮质膜
以及蚂蚁如何被用于更高级的细胞功能,如纤毛ATP调节影响
呼吸道水化和纤毛跳动。慢性阻塞性肺疾病是美国吸烟导致的第三大死因
(Cs)是导致疾病的主要侮辱。尽管哺乳动物研究仍在进行,但没有新的生物学
目标已经确定,目前的治疗方法对疾病进展或死亡率的影响有限。我
利用了一种遗传上易驯化的模型系统--盘状网柄蠕虫--的力量,
作为肺部生物学的基因选择发现工具。我鉴定了人蚂蚁(肺中存在ANT1和ANT2)
作为对CS诱导的人支气管上皮细胞死亡的保护作用。蚂蚁是一种线粒体
在线粒体代谢和ATP动态平衡中发挥积极作用的ADP/ATP转运体。而当
为了探索蚂蚁在人类呼吸道组织中的定位,我做了一个有趣的观察,除了
线粒体定位、人ANT1和ANT2定位于人活动纤毛质膜
呼吸道和分离的原代呼吸道细胞(正常人支气管上皮细胞,NHBE)。GFP-标记
腺病毒ANT1和ANT2也进入原发NHBE和ANT1的睫状膜(和线粒体)
经Western分析,ANT2在孤立的人睫状轴丝中存在。此外,ANT2特别指出
在CS的情况下,增强呼吸道表面的水合作用并保留纤毛搏动频率。这个早期的职业生涯
Proposal回答了以下问题:人类ANT1和ANT2如何定位于血浆
呼吸道上皮膜;质膜与线粒体蚂蚁如何调节呼吸道
纤毛呼吸道上皮的代谢、气道水化和纤毛功能;ANT2的影响是什么?
通过小鼠疾病模型研究呼吸道功能障碍和慢性阻塞性肺疾病发展的功能丧失和获得
鉴于其对呼吸道上皮的保护表型。这将使用以下组合来实现
分子工具、蚂蚁异构体基因修饰、细胞和组织成像、细胞的实时分析
新陈代谢、呼吸道水合作用和睫毛功能的评估以及与烟雾小鼠模型的相关性
曝光。归根结底,ANT在肺部疾病中的作用还没有被描述,治疗操作也没有。
它的生物学可能会让我们把细胞推向更健康的状态。这里探讨的核心生物学主题很可能
具有广泛的适用性,并对其他肺部疾病产生影响。
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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Corrine R Kliment其他文献
Corrine R Kliment的其他文献
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{{ truncateString('Corrine R Kliment', 18)}}的其他基金
The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
- 批准号:
10633608 - 财政年份:2023
- 资助金额:
$ 16.25万 - 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
- 批准号:
10459434 - 财政年份:2018
- 资助金额:
$ 16.25万 - 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
- 批准号:
10226893 - 财政年份:2018
- 资助金额:
$ 16.25万 - 项目类别:
Mitochondrial Genes as New Targets in the Protection of Airway Epithelial Cells Against Cigarette Smoke
线粒体基因作为保护气道上皮细胞免受香烟烟雾侵害的新靶标
- 批准号:
9192357 - 财政年份:2016
- 资助金额:
$ 16.25万 - 项目类别:
Extracellular Matrix Components, Oxidants and Antioxidants in Pulmonary Fibrosis
肺纤维化中的细胞外基质成分、氧化剂和抗氧化剂
- 批准号:
7679379 - 财政年份:2007
- 资助金额:
$ 16.25万 - 项目类别:
Extracellular Matrix Components, Oxidants and Antioxidants in Pulmonary Fibrosis
肺纤维化中的细胞外基质成分、氧化剂和抗氧化剂
- 批准号:
7503397 - 财政年份:2007
- 资助金额:
$ 16.25万 - 项目类别:
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