Early Origins of Chronic Lung Disease: Outcomes into the Fifth Decade of Life

慢性肺病的早期起源：生命第五个十年的结果

• 批准号: 10610445
• 负责人: Stefano Guerra
• 金额: $ 151.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610445
• 关键词: Acceleration; Address; Adult; Age; Anatomy; Asthma; Biological Assay; Birth; Blood specimen; Cells; Child; Childhood; Childhood Asthma; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Cohort Studies; Cryopreservation; Data; Development; Diagnosis; Disease; Environmental Exposure; Epidemiology; Epigenetic Process; Extrinsic asthma; Foundations; Functional disorder; Gene Expression; Generations; Genes; Health Care Costs; Image; Immunologics; Infant; Insulin; Life; Link; Lower respiratory tract structure; Lung; Metabolic; Minority; Molecular; Morbidity - disease rate; Natural History; Nutritional; Obstructive Lung Diseases; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Plasma; Plethysmography; Population Study; Pregnancy; Prevention; Primary Prevention; Process; Recording of previous events; Research; Respiratory Disease; Respiratory Mucosa; Respiratory Signs and Symptoms; Respiratory syncytial virus; Rhinitis; Risk; Risk Factors; Sampling; Serum; Smoker; Smoking; Spirometry; Sputum; Structure; Technology; Time; Total Lung Capacity; Virus Diseases; Weight Gain; Wheezing; Work; X-Ray Computed Tomography; airway inflammation; airway obstruction; asthma prevention; asthmatic; cell type; chronic respiratory disease; clinical phenotype; cohort; efficacious treatment; follow-up; in utero; indexing; instrument; lung volume; metabolomics; mortality; novel; prospective; pulmonary function; pulmonary function decline; respiratory

Asthma, chronic obstructive pulmonary disease (COPD) and a restrictive spirometry pattern (RSP) are strongly associated with increased morbidity and mortality burden. Recent discoveries strongly suggest that the roots of many cases of asthma, COPD and RSP in adulthood can be found during early life. Prevention of these heterogeneous conditions, for which no cure currently exists, requires a thorough understanding of the natural history and mechanistic pathways that underlie their distinct clinical phenotypes. The Tucson Children's Respiratory Study (TCRS) has already made major contributions to our understanding of the natural history of asthma and of lung function trajectories and, as its participants are entering their fifth decade, is now poised to investigate, prospectively, the early risk factors for asthma, COPD and RSP as well as the molecular basis of their distinct clinical phenotypes. While the origins of atopic asthma (T2) are well established, the origins of non-T2 asthma, which is overrepresented among severe asthmatics and for which no efficacious treatment is available, are less well known. We recently showed that both high serum insulin and non-atopic rhinitis at the age of six years are strong, separate predictors of asthma from childhood up to age 36 years. These findings offer exciting new avenues to understand the pathogenesis of non-T2 asthma based on its natural history. Here, we propose to use state-of-the-art single-cell epigenetic and gene expression technologies to compare the cell type distribution in sputum of participants with and without these two early life risk factors. Regarding COPD, our recent findings suggest that at least half of all patients diagnosed with the disease do not show accelerated lung function decline during adult life, suggesting that airflow limitation had its origins in low airway function trajectories starting in childhood. We now propose to use CT imaging to determine the anatomical features of the persistently low airway function trajectory. In addition, we showed that smokers who had confirmed lower respiratory tract illnesses due to respiratory syncytial virus (RSV) in early life are at increased risk of having chronic respiratory symptoms in the third decade of life. We now propose to use data into the fifth decade of life to ascertain if the RSV-smoking interaction explains why only a minority of smokers develop COPD. Finally, we will investigate the hypothesis that major risk factors for RSP are nutritional problems in- utero and during childhood. We will address 3 specific aims: 1. To assess the cellular and molecular endotypes and the continued influence of early life risk factors on phenotypes of asthma from childhood into mid-adult life. 2. To assess the continued influence of early life risk factors and the clinical, physiological, and airway structural alterations of incipient early COPD in mid-adult life. 3. To assess the influence of early life risk factors on plethysmography-defined lung restriction in mid-adult life. As the only birth cohort with hundreds of non- selected participants followed from birth into the fifth decade of life, the TCRS offers a unique opportunity to investigate the potential disease mechanisms for the early origins of asthma, COPD, and RSP in adult life.

哮喘、慢性阻塞性肺病 (COPD) 和限制性肺量测定模式 (RSP) 与 与发病率和死亡率负担增加有关。最近的发现强烈表明， 许多成年期哮喘、慢性阻塞性肺病 (COPD) 和 RSP 病例可以在生命早期发现。预防这些 目前尚无治愈方法，需要对自然条件有透彻的了解 其独特临床表型的历史和机制途径。图森儿童医院 呼吸研究（TCRS）已经为我们理解自然历史做出了重大贡献 哮喘和肺功能轨迹，随着参与者进入第五个十年，现在准备 前瞻性研究哮喘、COPD 和 RSP 的早期危险因素以及分子基础 他们独特的临床表型。虽然特应性哮喘 (T2) 的起源已经明确，但 非 T2 哮喘，在严重哮喘患者中所占比例过高，并且目前尚无有效的治疗方法 可用，但不太为人所知。我们最近表明，高血清胰岛素和非特应性鼻炎 六岁是从儿童期到 36 岁哮喘的强有力、独立的预测因素。这些发现 为根据非 T2 哮喘的自然史了解非 T2 哮喘的发病机制提供了令人兴奋的新途径。 在这里，我们建议使用最先进的单细胞表观遗传和基因表达技术来比较 有和没有这两种早期生命危险因素的参与者痰中的细胞类型分布。关于 慢性阻塞性肺病，我们最近的研究结果表明，至少一半被诊断患有该疾病的患者没有表现出 成年后肺功能加速衰退，表明气流受限起源于低气道 功能轨迹从童年开始。我们现在建议使用 CT 成像来确定解剖学 持续低气道功能轨迹的特征。此外，我们还发现吸烟者 生命早期因呼吸道合胞病毒 (RSV) 导致的下呼吸道疾病确诊人数增加 在三十岁的时候出现慢性呼吸道症状的风险。我们现在建议使用数据 生命的第五个十年，以确定 RSV 与吸烟的相互作用是否可以解释为什么只有少数吸烟者会出现这种情况 慢性阻塞性肺病。最后，我们将研究以下假设：RSP 的主要风险因素是以下方面的营养问题： 子宫内和童年时期。我们将实现 3 个具体目标： 1. 评估细胞和分子内型 以及早期生活危险因素对从儿童期到中年期哮喘表型的持续影响。 2. 评估早期生命危险因素以及临床、生理和气道的持续影响 中年早期慢性阻塞性肺病的结构改变。 3. 评估早期生命危险因素的影响 体积描记法定义的中年肺限制。作为唯一一个拥有数百名非 选定的参与者从出生到五十岁，TCRS 提供了一个独特的机会 研究成人生活中哮喘、COPD 和 RSP 早期起源的潜在疾病机制。

项目成果

Epithelial cell responses to rhinovirus identify an early-life-onset asthma phenotype in adults.

• DOI: 10.1016/j.jaci.2022.03.020
• 发表时间: 2022-09
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Chang, Eugene H.;Pouladi, Nima;Guerra, Stefano;Jandova, Jana;Kim, Alexander;Li, Haiquan;Li, Jianrong;Morgan, Wayne;Stern, Debra A.;Willis, Amanda L.;Lussier, Yves A.;Martinez, Fernando D.
• 通讯作者: Martinez, Fernando D.

Association between the CDHR3 rs6967330 risk allele and chronic rhinosinusitis.

• DOI: 10.1016/j.jaci.2016.10.027
• 发表时间: 2017-06
• 期刊: The Journal of allergy and clinical immunology
• 作者: Chang EH;Willis AL;McCrary HC;Noutsios GT;Le CH;Chiu AG;Mansfield CJ;Reed DR;Brooks SG;Adappa ND;Palmer JN;Cohen NG;Stern DA;Guerra S;Martinez FD
• 通讯作者: Martinez FD

Bending the Twig Does the Tree Incline: Lung Function after Lower Respiratory Tract Illness in Infancy.

弯曲树枝会使树倾斜：婴儿期下呼吸道疾病后的肺功能。

• DOI: 10.1164/rccm.201611-2325ed
• 发表时间: 2017
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Martinez,FernandoD

RV-C infections result in greater clinical symptoms and epithelial responses compared to RV-A infections in patients with CRS.

• DOI: 10.1111/all.14435
• 发表时间: 2020-12
• 期刊: Allergy
• 影响因子: 12.4

Alternaria sensitisation at age 6 years is associated with subsequent airway hyper-responsiveness in non-asthmatics.

非哮喘患者 6 岁时的链格孢过敏与随后的气道高反应性相关。

• DOI: 10.1136/thoraxjnl-2017-210325
• 发表时间: 2018
• 期刊: Thorax
• 影响因子: 10
• 作者: Hiranrattana,Anunya;Stern,DebraA;Guerra,Stefano;Halonen,Marilyn;Wright,AnneL;Daines,Michael;Martinez,FernandoD;Morgan,WayneJ
• 通讯作者: Morgan,WayneJ