Sputum-Based Profiling to Predict Cystic Fibrosis Exacerbations

基于痰液分析来预测囊性纤维化恶化

• 批准号: 10237397
• 负责人: Clemente Britto-Leon
• 金额: $ 8.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237397
• 关键词: Acute; Acute Lung Injury; Adult; Airway Disease; Award; Bioinformatics; Biological Assay; Biological Markers; Cells; Chemistry; Clinical; Clinical Data; Clinical Trials; Cox Proportional Hazards Models; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis sputum; Data; Data Analyses; Deterioration; Diagnosis; Diagnostic; Enzyme-Linked Immunosorbent Assay; Epithelial; Event; Exhibits; Funding; Future; Gene Expression; Genes; Genetic Diseases; Goals; Home; Hospitalization; Host Defense; Immune; Immunology; Individual; Influenza; Influenza A virus; Innate Immune Response; Interferons; Laboratories; Life; Link; Lung; Lung Inflammation; Lung diseases; Measures; Mentored Research Scientist Development Award; Methodology; Microbiology; Morbidity - disease rate; Mus; Mutation; Nasal Epithelium; National Heart, Lung, and Blood Institute; Palate; Patient Care; Patient Schedules; Patient Selection; Patients; Pharmaceutical Preparations; Property; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Respiratory Tract Infections; Risk; Role; Sampling; Signal Transduction; Sputum; Subgroup; System; Testing; Therapeutic Intervention; Translating; United States; Visit; Work; airway inflammation; base; children with cystic fibrosis; clinically relevant; cohort; cystic fibrosis patients; high risk; immune activation; immunoregulation; macrophage; monocyte; mortality; neutrophil; pathogen; prevent; programs; pulmonary function; pulmonary function decline; receptor; respiratory; respiratory pathogen; single-cell RNA sequencing; therapeutic development; therapeutic target; tool; transcriptome; transcriptomics

PROJECT SUMMARY Cystic fibrosis (CF) is the most common life-shortening genetic disease in the United States. The primary cause of mortality in CF is lung disease, characterized by airway inflammation and lung function decline. CF acute exacerbations (AE) are episodes of rapid clinical deterioration, often associated with worsening airway inflammation and lung function. Limited data link sputum biomarkers and AE, but these markers are not predictive of future events. There are even fewer data analyzing sputum cellular components to diagnose or characterize AE. The lack of readily available noninvasive markers of AE is a critical unmet need, as they could guide therapeutic interventions to minimize morbidity, and facilitate patient selection for clinical trials in an era of accelerated therapeutic developments in CF. We previously showed that airway concentrations of host defense protein Short Palate Lung epithelium Clone 1 (SPLUNC1) are tightly regulated by airway inflammation and respiratory pathogens. Continuing this work on the soluble fraction of sputum, we show in preliminary data that SPLUNC1 is acutely decreased in AE and that stable CF subjects with low basal SPLUNC1 levels have a 6-fold increase in AE likelihood within 60 days. We are now integrating those studies with data from the cellular component of sputum, where preliminary data using single-cell RNA sequencing (scRNAseq) show that CF neutrophils and macrophages exhibit distinct transcriptomic profiles that separate AE from stable states. Our overall hypothesis is that a sputum panel combining soluble (SPLUNC1) and cellular (single- cell transcriptome profile) markers can robustly diagnose and predict early airway inflammation during AE in CF. We will test this using the following specific aims: Aim 1: Establish SPLUNC1 as a diagnostic tool and predictor of AE in CF; Aim 2: Define the AE-associated sputum single-cell transcriptome profile and its ability to predict AE; and Aim 3: Determine if a combined SPLUNC1-scRNAseq panel is a better predictor of AE than FEV1. This proposal is a translational application of mechanistic data generated during my K01 award. Our K01 work uncovered the immunomodulatory role of SPLUNC1 in lung host-pathogen interactions. The goal of this project is to investigate the link between SPLUNC1's immune properties and the sputum cell transcriptomic changes that occur during immune activation in AE. The R03 Award will support complementary studies for my NHLBI-K01-funded work as I apply for my first R01, focused on SPLUNC1-controlled mechanisms of acute lung injury during respiratory infections. The proposed work will translate our findings into clinically relevant tools that inform patient care and minimize the impact of AE for patients with CF and other airway diseases.

项目摘要 囊性纤维化（CF）是美国最常见的遗传疾病。主要 CF死亡率的原因是肺部疾病，其特征是气道炎症和肺功能下降。 CF 急性加重（AE）是快速临床恶化的发作，通常与气道恶化有关 炎症和肺功能。有限的数据链接痰物生物标志物和AE，但这些标记不是预测性的 未来事件。分析痰细胞成分的数据甚至更少，以诊断或表征 Ae。 AE缺乏随时可用的无创标志物是一个至关重要的未满足需求，因为他们可以指导 治疗干预措施以最大程度地减少发病率，并促进患者在一个时代的临床试验中选择 CF的加速治疗发展。 我们先前表明，宿主防御蛋白短pa肺肺上皮的气道浓度 克隆1（Splunc1）受气道炎症和呼吸道病原体严格调节。继续这个 在痰的可溶性部分上的工作，我们在初步数据中显示，splunc1在AE中急剧减少 稳定的CF受试者具有低基础Splunc1水平的AE可能性增加了6倍 天。我们现在正在将这些研究与来自痰液的细胞成分的数据相结合，该研究是初步的 使用单细胞RNA测序（SCRNASEQ）的数据表明，CF中性粒细胞和巨噬细胞表现出不同的 将AE与稳定状态分开的转录组曲线。 我们的总体假设是将可溶性（Splunc1）和细胞（单次 - 细胞转录组轮廓）标记可以牢固地诊断并预测早期气道炎症 AE在CF中。我们将使用以下特定目的进行测试：目标1：建立Splunc1作为诊断工具 和CF中AE的预测因子； AIM 2：定义与AE相关的痰液单细胞转录组轮廓及其 预测AE的能力； AIM 3：确定组合的Splunc1-Scrnaseq面板是否是AE的更好预测指标 比FEV1。 该提案是我K01奖中生成的机械数据的翻译应用。我们的K01 工作发现了Splunc1在肺宿主 - 病原体相互作用中的免疫调节作用。目标的目标 项目是研究Splunc1的免疫特性与痰细胞转录组之间的联系 AE免疫激活期间发生的变化。 R03奖将支持我的互补研究 NHLBI-K01资助的工作申请了我的第一个R01，重点是急性肺的Splunc1控制机制 呼吸道感染期间的损伤。拟议的工作将使我们的发现转化为临床相关的工具 通知患者护理，并最大程度地减少AE对CF和其他气道疾病患者的影响。

项目成果

SPLUNC1: a novel marker of cystic fibrosis exacerbations.

• DOI: 10.1183/13993003.00507-2020
• 发表时间: 2021-11
• 期刊: The European respiratory journal
• 作者: Khanal S;Webster M;Niu N;Zielonka J;Nunez M;Chupp G;Slade MD;Cohn L;Sauler M;Gomez JL;Tarran R;Sharma L;Dela Cruz CS;Egan M;Laguna T;Britto CJ
• 通讯作者: Britto CJ