Ancillary SOURCE Study: Characterization of Small Airway Basal Cell Biology in Early COPD

辅助来源研究：早期 COPD 中小气道基底细胞生物学的特征

• 批准号: 10736644
• 负责人: RONALD G CRYSTAL
• 金额: $ 80万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736644
• 关键词: Affect; Age; Air; Ancillary Study; Basal Cell; Biological; Biological Markers; Biological Process; Biology; Bone Morphogenetic Proteins; Bronchoscopy; Cell Differentiation process; Cells; Cellular biology; Characteristics; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Data; Data; Disease; Disease Progression; Functional disorder; Funding; Future; Gene Expression; Genes; Goals; Goblet Cells; Gold; Human; Hyperplasia; Image; Impairment; In Vitro; Individual; Institution; Irrigation; Knowledge; Liquid substance; Mediating; Mediator; Metaplasia; Mucous body substance; National Heart, Lung, and Blood Institute; Natural regeneration; Observational Study; Participant; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiological; Physiology; Proteins; Questionnaires; RNA; Resources; Role; Sampling; Serum; Signal Pathway; Site; Smoker; Squamous Differentiation; Squamous Metaplasia; Structure; Testing; Therapeutic Intervention; Undifferentiated; Up-Regulation; airway epithelium; biobank; cell type; clinical phenotype; design; non-smoking; overexpression; pharmacologic; prevent; receptor; small airways disease; stem cell differentiation; stem cells; targeted treatment; therapeutic target; transcription factor

Abstract. This is an ancillary study to SOURCE (SPIROMICS Study of Early COPD Progression, NHLBI HL144718), an observational study of the early manifestations of chronic obstructive pulmonary disease (COPD). Based on the knowledge that the small airway epithelium (SAE) is the earliest site of the pathology of COPD, the focus of this ancillary proposal is to characterize the disordered SAE differentiation in SOURCE participants and correlate this biologic dysfunction with the abnormal early COPD small airway clinical phenotypes characterized in SOURCE. We will capitalize on the availability of resources from SOURCE for use in our study, including: detailed clinical phenotyping of small airway structure and function, with serum, lavage fluid, SAE cytopreps, SAE RNA, and SAE basal stem/progenitor cells obtained by bronchoscopy from n=80 individuals with early COPD ages 30-55, and n=20 normal controls. As an additional control, we will provide parallel clinical data and biologic samples from our BioBank n=10 healthy smokers. Based on our observations that in early COPD, SAE basal stem/progenitor cells have a decreased capacity to form a normal differentiated SAE, preliminary data demonstrating that BMP4 and SPDEF are upregulated in the SAE in early COPD smokers and that BMP4 induces squamous metaplasia and SPDEF induces goblet cell hyperplasia, the proposed studies will characterize the role of BMP4 and SPDEF in the pathogenesis of the disordered small airway differentiation in early COPD. We hypothesize that early COPD is characterized, in part, by SAE upregulation of BMP4 and SPDEF which, in turn, contribute to the clinical abnormalities of the small airways that characterize early COPD. The results will help determine if BMP4 and SPDEF and/or their driver genes and/or downstream signaling pathways are potential targets for future therapeutic intervention to reverse/prevent the small airway abnormalities that characterize early COPD. We propose 3 specific aims. Aim 1: To characterize the disordered SAE in early COPD and evaluate the hypothesis that SAE basal cells (BC) from individuals with early COPD have a reduced capacity to differentiate into a normal SAE as assessed in vitro using air-liquid interface cultures. Aim 2: To examine the hypothesis that the disordered SAE BC differentiation in early COPD is caused, in part, by SAE overexpression of BMP4 and SPDEF, resulting in activation of their respective receptor downstream signaling pathways and consequent abnormal SAE differentiation of squamous metaplasia and goblet cell hyperplasia. Aim 3: To test the hypothesis that diminished small airway epithelial BC differentiation and BMP4- and SPDEF- mediated biologic parameters correlate with the clinical parameters of small airway structure and function in the same SOURCE participants with early COPD.

抽象的。这是一项用于来源的辅助研究（早期COPD进展，NHLBI的螺旋学研究 HL144718），一项对慢性阻塞性肺疾病早期表现的观察性研究 （COPD）。基于知道小气道上皮（SAE）是最早的地点 COPD的病理学，该辅助建议的重点是表征无序的SAE 源参与者的分化并将这种生物功能障碍与异常相关 早期COPD小气道临床表型以源为特征。我们将利用 在我们的研究中提供资源的可用性，包括：详细的临床表型 小型气道结构和功能，具有血清，灌洗液，SAE Cytopreps，SAE RNA和SAE基础 通过支气管镜检查获得的茎/祖细胞，来自n = 80个患者，年龄为30-55岁，并且 n = 20个正常对照。作为额外的控制，我们将提供平行的临床数据和生物样品 来自我们的生物库n = 10名健康吸烟者。基于我们的观察，在早期COPD中，SAE基础 茎/祖细胞的能力降低，形成正常分化的SAE初步数据 证明BMP4和SPDEF在早期吸烟者的SAE中被上调，并且BMP4 诱导鳞状化生和SPDEF诱导杯状细胞增生，拟议的研究将 表征BMP4和SPDEF在无序小气道发病机理中的作用 早期COPD的分化。我们假设早期COPD的特征是SAE的特征 BMP4和SPDEF的上调反过来促进 特征早期COPD的小气道。结果将有助于确定BMP4和SPDEF和/或 他们的驱动基因和/或下游信号通路是未来治疗的潜在目标 干预以逆转/防止早期COPD表征的小气道异常。我们建议 3个具体目标。目标1：在早期COPD中表征无序的SAE并评估假设 来自患有早期COPD的个体的SAE基底细胞（BC）具有分化为A的能力降低 正常SAE使用空气界面培养物在体外评估。目的2：探讨以下假设 早期COPD中的SAE BC分化无序是由BMP4的SAE过表达引起的 和SPDEF，导致其各自的受体下游信号通路和 因此，鳞状化生和杯状细胞增生的异常SAE分化。目标3：到 测试假设减少了小气道上皮BC分化以及BMP4-和SPDEF- 介导的生物学参数与小气道结构和功能的临床参数相关 在早期COPD的同一来源参与者中。