Mucus Matters: Mucociliary Physiology in Pulmonary Fibrosis

粘液很重要：肺纤维化中的粘液纤毛生理学

• 批准号: 9918159
• 负责人: Jacelyn Emily Peabody Lever
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2021-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918159
• 关键词: Accounting; Address; Affect; Alveolar; Anatomy; Animal Model; Basic Science; Bleomycin; Blood capillaries; Chronic; Chronic Obstructive Airway Disease; Cilia; Clinical; Clinical Research; Colloids; Complement; Cyst; Cystic Fibrosis; Data; Deposition; Development; Diagnosis; Diffuse; Disease; Disease model; Doctor of Philosophy; Epithelial; Epithelium; Evaluation; Exhibits; Extracellular Matrix; Ferrets; Fibrosis; Fostering; Foundations; Frequencies; Functional disorder; Future; Gases; Gel; Genetic; Genotype; Gland; Histologic; Human; Hydroxyproline; Impairment; Incidence; Individual; Inhalation; Interstitial Lung Diseases; Intervention; Knowledge; Label; Life; Link; Liquid substance; Lung; MUC5B gene; Malignant Neoplasms; Measurement; Measures; Medical; Mentorship; Microanatomy; Mission; Modeling; Molecular; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Mus; National Heart, Lung, and Blood Institute; Pathogenesis; Pathogenicity; Pathologic; Patients; Peripheral; Pharmacology; Phenotype; Physicians; Physiological; Physiology; Positioning Attribute; Pre-Clinical Model; Prevalence; Production; Pulmonary Fibrosis; Pulmonology; Pyocyanine; Regulation; Respiratory Failure; Respiratory physiology; Risk; Risk Factors; Rodent; Role; Scientist; Severities; Severity of illness; Solid; Source; Structure of parenchyma of lung; Sulfur; System; Techniques; Testing; Time; Training; Variant; Viscosity; airway epithelium; airway surface liquid; career; career development; curative treatments; disorder risk; experimental study; functional loss; gain of function; genome wide association study; high risk; human disease; idiopathic pulmonary fibrosis; improved; in vivo; mortality; mucus clearance; new therapeutic target; novel; outcome forecast; overexpression; patient stratification; pre-clinical; promoter; repaired; risk variant

PROJECT SUMMARY This F31 application is for support of Jacelyn Peabody’s MD/ Ph.D. training. Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that results in loss of functional alveolar-capillary units leading to impaired gas exchange and respiratory failure. IPF has a worse prognosis than most cancers: the five-year mortality rate is 50-70%, and there are no curative medical therapies. The most significant risk factor for developing IPF is a common, gain-of-function MUC5B promoter variant rs35705950, accounting for at least 30% of the total risk. The MUC5B variant is also predictive of those with preclinical forms of pulmonary fibrosis (pre- PF), which suggests that IPF risk variants may be helpful in identifying subjects with higher risk of disease development. There could be a window of opportunity for targeted intervention, before significant loss of viable lung parenchyma has occurred in at-risk individuals with preclinical stages of fibrotic disease. Though MUC5B has been associated with IPF, the mechanistic role of MUC5B in IPF pathogenesis is unknown. Our central hypothesis is that MUC5B abnormalities contribute to pathologic mucus and decreased mucociliary clearance (MCC), which may help initiate and propagate fibrosis in IPF. Our objective is to elucidate the mechanisms by which abnormal mucociliary physiology influence pulmonary fibrosis in (1) novel bleomycin- induced pulmonary fibrosis ferret models and (2) human IPF patients stratified by rs35705950 genotype and disease severity. These aims are in line with the mission of the NHLBI because they address important basic and translational aspects for the interplay between mucociliary dysregulation and the development of pulmonary fibrosis. As a result of the proposed studies, we expect to develop novel targets within the molecular regulation of MUC5B expression or therapies to improve MCC such as mucolytics for intervention in the pre-PF to IPF transition and in IPF patients, which could alter the disease course and improve both quality and duration of life. This proposal will provide a solid training period for Jacelyn Peabody (PI) under the mentorship of Drs. Steven Rowe (Sponsor) and Victor Thannickal (Co-sponsor) which will foster her career development as an astute and creative physician-scientist. Successful completion will position her for an independent career investigating disorders of mucociliary clearance and mechanisms of fibrosis using cutting-edge techniques.

项目总结 这份F31申请书是为了支持杰斯琳·皮博迪的医学博士培训。特发性肺纤维化(IPF) 是一种慢性进行性间质性肺疾病，导致功能性肺泡-毛细血管单位丧失 导致气体交换受损和呼吸衰竭。IPF的预后比大多数癌症都要差：5年 死亡率为50%-70%，而且没有根治的药物疗法。最重要的风险因素是 发展中的IPF是一种常见的、功能获得的MUC5B启动子突变体rs35705950，至少占30% 总风险的一部分。MUC5B变异体也可以预测那些具有临床前形式的肺纤维化(前 Pf)，这表明IPF风险变量可能有助于识别疾病风险较高的受试者 发展。在严重丧失可行性之前，可能会有一段时间进行有针对性的干预 肺实质出现在临床前纤维性疾病的高危人群中。 尽管MUC5B与IPF相关，但MUC5B在IPF发病机制中的作用尚不清楚。 我们的中心假设是，MUC5B异常有助于病理性粘液和粘液纤毛减少 清除(MCC)，这可能有助于启动和传播纤维化在IPF。我们的目标是澄清 粘液纤毛生理异常影响肺纤维化的机制：(1)新型博莱霉素钠 诱导的肺纤维化雪貂模型和(2)按rs35705950基因和rs35705950基因和 疾病的严重性。这些目标与NHLBI的使命是一致的，因为它们涉及重要的基本 粘液纤毛调节失调与肺纤维化发展相互作用的翻译研究 纤维化症。作为拟议研究的结果，我们期望在分子调控范围内开发新的靶点。 MUC5B的表达或改善MCC的治疗，如用于干预Pre-PF到IPF的粘液溶解药物 在过渡和IPF患者中，这可能会改变疾病的进程，改善生活质量和持续时间。 这项提议将在Steven博士的指导下为Jacelyn Peabody(PI)提供一个坚实的训练期 Rowe(赞助商)和Victor Thanickal(共同赞助商)，这将促进她作为一名精明和 富有创造力的内科医生兼科学家。成功完成学业将为她进行独立的职业调查奠定基础 用尖端技术研究粘液纤毛清除障碍和纤维化机制。