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。这是一项对SOURCE（COPD早期进展的SPIROMICS研究，NHLBI）的辅助研究 HL 144718），一项慢性阻塞性肺疾病早期表现的观察性研究 （COPD）。基于小气道上皮（SAE）是最早发生SAE的部位这一认识， COPD的病理学，本辅助建议的重点是描述疾病性SAE的特征 在源参与者的分化，并将这种生物功能障碍与异常 SOURCE中描述的早期COPD小气道临床表型。我们将利用 来源的资源可用于我们的研究，包括： 小气道结构和功能，包括血清、灌洗液、SAE细胞计数、SAE RNA和SAE基础 通过支气管镜检查从n=80名30-55岁的早期COPD个体获得干/祖细胞，和 n=20名正常对照。作为额外的对照，我们将提供平行的临床数据和生物样本 n=10名健康吸烟者。根据我们的观察，在早期COPD中，SAE基础 初步数据显示，干细胞/祖细胞形成正常分化SAE的能力下降 证明BMP 4和SPDEF在早期COPD吸烟者的SAE中上调， 诱导鳞状化生和SPDEF诱导杯状细胞增生，拟定的研究将 描述BMP 4和SPDEF在小气道疾病发病机制中的作用 早期COPD的区别我们假设早期COPD的部分特征是SAE BMP 4和SPDEF的上调，这反过来又导致了 小气道是早期COPD的特征。结果将有助于确定BMP 4和SPDEF和/或 它们的驱动基因和/或下游信号通路是未来治疗的潜在靶点。 干预以逆转/预防作为早期COPD特征的小气道异常。我们提出 3具体目标目的1：描述早期COPD中的紊乱性SAE并评估假设 来自早期COPD个体的SAE基底细胞（BC）分化为正常人的能力降低， 使用气液界面培养物在体外评估的正常SAE。目的2：检验假设， 早期COPD中SAE BC分化紊乱部分是由于BMP 4的SAE过表达引起的， 和SPDEF，导致其各自受体下游信号传导途径的激活， 鳞状化生和杯状细胞增生的SAE分化异常。目标3： 检验减少小气道上皮BC分化以及BMP 4和SPDEF的假设 介导的生物学参数与小气道结构和功能的临床参数相关 在同一来源的早期COPD参与者中。