Exhaustion of Airway Progenitor Cells Indicates Susceptibility to COPD

气道祖细胞耗竭表明对慢性阻塞性肺病 (COPD) 的易感性

• 批准号: 9302509
• 负责人: Moumita Ghosh
• 金额: $ 39.47万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302509
• 关键词: Affect; Air; Basal Cell; Biological Markers; Biopsy; Cause of Death; Cell physiology; Cells; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Complement; Cross-Sectional Studies; DNA Methylation; Data; Development; Diagnosis; Disease; Disease susceptibility; Early treatment; Epithelial Cells; Epithelium; Functional disorder; Funding; Gene Expression; Generations; Health; Heritability; Home environment; Impairment; In Vitro; Individual; Injury; Knowledge; Liquid substance; Longitudinal Studies; Lung; Maintenance; Measurement; Measures; Molecular; Mucous body substance; Phenotype; Population; Predisposition; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Resistance; Respiratory physiology; Role; Smoker; Stem cells; Structure; Subgroup; Symptoms; Testing; Tissues; United States; United States National Institutes of Health; Whole Organism; Withholding Treatment; airway obstruction; assault; base; cell type; cigarette smoking; clinical phenotype; cost; exhaust; exhaustion; improved; innovation; prevent; progenitor; prospective; public health relevance; resilience; response; self-renewal; smoking cessation; transcriptome sequencing

 DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is one of the most important public health problems in the United States, because it affects over 24 million people, costs $50 billion per year and is the third leading cause of death. It has been known for almost 40 years that only ~15% of susceptible smokers will develop COPD. Despite this knowledge, very little progress has been made in identifying factors that contribute to susceptibility and how these factors manifest during pre-symptomatic stages of disease (Pre-COPD). Airway progenitor cells are critical for the maintenance of lung health because of their ability to restore normal airway structure and function following injury. The inability of the lungto return to normal in COPD suggests that airway progenitor function is impaired. Progenitor cells are defined by the ability to self-renew, meaning that they are able to replenish themselves, and by the ability to differentiate into all cell-types that normally populate their home tissue, a characteristic referred to as multipotentiality. We leveraged the NIH-funded Biomarker Study to determine the role of airway progenitor cells in COPD. Our preliminary data show that progenitor counts, self-renewal and multipotentiality are all decreased in COPD. Progenitor dysfunction manifests in vitro during air-liquid interface culture by generation of an abnormal epithelium characterized by altered ratios of mucous, basal and ciliated cells, and increased secretion of mucus. COPD develops slowly over years as small airways narrow and disappear causing lung function to decline. Despite the importance of this long pre- symptomatic period there is no definition of "Pre-COPD". Our preliminary data indicate that progenitor counts can be used to diagnose Pre-COPD, because they separate current/ex-smokers into those with high-normal or low-normal lung function. Based on these data, we hypothesize that progenitor exhaustion, identified by low progenitor counts, characterizes a subgroup of "normal" subjects with Pre-COPD. We also hypothesize the converse that progenitor vigor, identified by high progenitor counts, characterizes a subgroup with resilience and lung health. This proposal will use a cross-sectional approach in Specific Aim 1 to determine the measure of progenitor function (e.g. count, self-renewal or mulltipotentiality) or combination of measures that best define resilience and Pre-COPD. In Specific Aim 2 a longitudinal study will be used to examine whether subjects with Pre-COPD have an accelerated decline in lung function compared to resilient subjects. In both aims, extensive molecular and clinical data will be used to characterize resilience and Pre-COPD on the whole organism, cell and molecular levels. The most important innovation of this proposal is the concept that vigorous airway progenitors are necessary for resilience and lung health, and that exhausted progenitors make the lung susceptible to external assault and development of COPD. This concept could have a direct impact on preventing COPD by identifying those who are susceptible to the effects of cigarette smoke. Armed with this knowledge smoking cessation and early treatment efforts could be focused on people with Pre-COPD.

 描述（由适用提供）：慢性阻塞性肺疾病（COPD）是美国最重要的公共卫生问题之一，因为它影响了超过2400万人，每年耗资500亿美元，并且是第三大死亡原因。近40年来，只有约15％的易感吸烟者会发展COPD。尽管有这些知识，但在识别导致易感性的因素以及这些因素如何在疾病的症状阶段（PRECOPD）中表现出很少的进展。气道祖细胞对于维持肺部健康至关重要，因为它们能够恢复受伤后正常气道结构和功能。 COPD中肺部恢复正常的无力表明气道祖细胞功能受到损害。祖细胞由自我更新的能力定义，这意味着它们是我们利用NIH资助的生物标志物研究来确定气道祖细胞在COPD中的作用。我们的初步数据表明，COPD中的祖细胞计数，自我更新和多能性都得到了改善。祖细胞功能障碍在空气界面培养过程中通过产生异常上皮的体外表现，其特征是粘液，碱性和纤毛细胞的比例改变，并增加了粘液分泌。随着小气道狭窄而消失，COPD的发展缓慢，导致肺功能下降。尽管这个漫长的症状前期很重要，但没有对“ pre-opd”的定义。我们的初步数据表明祖细胞计数可用于诊断前COPD，因为它们将电流/EX-SMOKER分离为具有高正常或低正常肺功能的人。基于这些数据，我们假设由低祖细胞计数确定的祖细胞耗尽表征了具有前poPD的“正常”受试者的子组。我们还假设相反的是，祖细胞计数鉴定出的祖细胞活力是具有弹性和肺部健康的亚组。该提案将在特定目标1中使用横截面方法来确定祖细胞函数的测量（例如计数，自我更新或mulltipentiality性）或最佳定义弹性和前poPD的度量的组合。在特定目标2中，将使用纵向研究来检查与弹性受试者相比，患有前COPD的受试者肺功能是否会加速下降。在这两个目标中，都将使用广泛的分子数据和临床数据来表征整个生物体，细胞和分子水平的弹性和预先进行的。该提案最重要的创新是一个概念，即有剧烈的气道祖细胞对于弹性和肺部健康是必要的，并且疲惫的祖细胞使肺部容易受到COPD外部攻击和发展的影响。通过识别那些容易受到香烟烟雾影响的人，这个概念可能会直接影响防止COPD。有了这种知识，戒烟和早期治疗工作可以集中在前prepd的人身上。

项目成果

A Survey of Corticosteroid Dosing for Exacerbations of Chronic Obstructive Pulmonary Disease Requiring Assisted Ventilation.

需要辅助通气的慢性阻塞性肺疾病恶化时皮质类固醇剂量的调查。

• DOI: 10.15326/jcopdf.4.3.2016.0168
• 发表时间: 2017
• 期刊: Chronic obstructive pulmonary diseases (Miami, Fla.)
• 作者: Kiser,TyreeH;Sevransky,JonathanE;Krishnan,JerryA;Tonascia,James;Wise,RobertA;Checkley,William;Walsh,John;Sullivan,JamieB;Wilson,KevinC;Barker,Alan;Moss,Marc;Vandivier,RWilliam
• 通讯作者: Vandivier,RWilliam

Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism.

• DOI: 10.1097/ccm.0000000000003288
• 发表时间: 2018-10
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Kiser TH;Burnham EL;Clark B;Ho PM;Allen RR;Moss M;Vandivier RW
• 通讯作者: Vandivier RW

The Authors Reply.

• DOI: 10.1038/ki.2015.131
• 发表时间: 2015-07
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Dong Z

Repeated injury promotes tracheobronchial tissue stem cell attrition.

• DOI: 10.1002/sctm.21-0032
• 发表时间: 2021-12
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Ghosh M;Hill CL;Alsudayri A;Lallier SW;Hayes D Jr;Wijeratne S;Tan ZH;Chiang T;Mahoney JE;Carraro G;Stripp BR;Reynolds SD
• 通讯作者: Reynolds SD

Challenges Faced by Rural Primary Care Providers When Caring for COPD Patients in the Western United States.

美国西部农村初级保健提供者在照顾慢性阻塞性肺病患者时面临的挑战。

• DOI: 10.15326/jcopdf.2021.0215
• 发表时间: 2021
• 期刊: Chronic obstructive pulmonary diseases (Miami, Fla.)
• 作者: DiazDelValle,Fernando;Koff,PatriciaB;Min,Sung-Joon;Zakrajsek,JonathanK;Zittleman,Linda;Fernald,DouglasH;Nederveld,Andrea;Nease,DonaldE;Hunter,AlexisR;Moody,EricJ;MillerTemple,Kay;Niblock,JennyL;Grund,Chrysanne;Oser,Tam
• 通讯作者: Oser,Tam