Purines as Biomarkers of Respiratory Disease

呼吸系统疾病如囊性纤维化（CF）的特征在于一系列病理生理学变化， 从粘液分泌物脱水开始并继续到粘膜纤毛清除受损的变化， 慢性气道炎症和随后的肺损伤。这些变化的有效生物标志物是 迫切需要监测疾病进展，确定急性加重，并评估现有药物的疗效。 和新疗法。这个职业发展应用程序的目标是提供博士.查尔斯埃斯特 识别和评估呼出气冷凝液（EBC）中候选生物标志物所需的技能， 即使在幼儿中也可以简单且非侵入性地收集气道样本。埃丝特医生计划 克服了分析低浓度，可变稀释EBC的挑战，通过应用 液相色谱-串联质谱法（LC-MS/MS）。这项技术代表了一个高度 允许同时测量多个小分子灵敏且灵活的方法 生物标志物以及作为稀释标志物的尿素。在这项研究计划中，埃丝特博士将使用质量 光谱法，以确定和测试CF的两个关键方面的简单和非侵入性EBC生物标志物 气道病理生理学：嗜酸性气道炎症和气道粘液分泌物脱水。 基于已建立的生物标志物和代谢组学的靶向分析确定的潜在生物标志物 嗜酸性炎症和粘液脱水的体外模型的研究。测量协议将 使用LC-MS/MS开发，并在儿童和成人队列中评估有希望的生物标志物， 确定其可靠性和与公认的疾病病理生理学标志物的关系， 潜在的混淆因素。成功完成本提案中概述的研究计划不仅将 为将来研究CF的病理生理学和治疗方案提供重要工具，但 还提供以斯帖博士的技能和必要的经验，以发展职业生涯的鉴定， 检测呼吸系统疾病的非侵入性生物标志物。 相关性（参见说明）： 囊性纤维化的特征是肺内的疾病相关变化，Esther博士建议 开发简单和非侵入性的方法来检测这些变化，使用尖端技术， 质谱和呼出气冷凝物收集。这些方法的发展将提供 囊性纤维化和其他肺部疾病的临床管理和研究的宝贵工具。

Respiratory diseases such as cystic fibrosis (CF) are characterized by a cascade of pathophysiological changes starting with dehydration of mucus secretions and proceeding to impaired mucociliary clearance, chronic airway inflammation, and subsequent lung injury. Effective biomarkers of these changes are urgently needed to monitor disease progression, identify exacerbations, and evaluate the efficacy of existing and novel therapies. The goal of this career development application is to provide Dr. Charles Esther with the skills needed to identify and assess candidate biomarkers in exhaled breath condensate (EBC), an airway sample that can be collected simply and non-invasively even in young children. Dr. Esther plans to overcome the challenges of analyzing the low concentration, variable dilution EBC through application of liquid-chromatography-tandem mass spectrometry (LC-MS/MS). This technology represents a highly sensitive and flexible methodology that permits simultaneous measurement of multiple small molecule biomarkers as well as urea as a dilution marker. In this research proposal, Dr. Esther will use mass spectrometry to identify and test simple and non-invasive EBC biomarkers of two critical aspects of CF airways pathophysiology: neutrophilic airway inflammation and dehydration of airway mucus secretions. Potential biomarkers identified based on both targeted analyses of established biomarkers and metabolomic studies of in vitro models of neutrophilic inflammation and mucus dehydration. Measurement protocols will be developed using LC-MS/MS, and promising biomarkers assessed in a cohort of children and adults with to determine their reliability and relationship to accepted markers of disease pathophysiology and to identify potential confounders. Successful completion of the research plan outlined in this proposal will not only generate important tools for future research on the pathophysiology and therapeutic options for CF, but will also provide Dr. Esther with the skills and experiences necessary to develop a career in identification and testing of non-invasive biomarkers of respiratory disease. RELEVANCE (See instructions): Cystic fibrosis is characterized by disease related changes within the lung, and Dr. Esther proposes to develop simple and non-invasive methods to detect these changes using the cutting edge technologies of mass spectrometry and exhaled breath condensate collection. Development of these methods will provide invaluable tools for clinical management and research in cystic fibrosis and other lung diseases.