Pediatric Severe Asthma: Role of Oxidant Stress and Alveolar Macrophage Function

描述(由申请人提供)：本建议的目的是促进Anne Fitzpatrick博士的科学发展和实验室技能，使她能够成为一名具有临床翻译研究专业知识的独立研究员。菲茨帕特里克博士的长期目标是找出导致儿童严重哮喘的新的生物机制。实现这一目标不可或缺的步骤是：1)获得必要的实验室技能，使她能够进行独立的临床转化实验；2)参与哮喘儿童氧化应激和肺泡巨噬细胞(AM)功能的多学科机制研究。这一研究生涯奖将使菲茨帕特里克博士不仅可以发展她的研究技能和专业知识，而且还可以继续进行教学阶段的研究，这对她发展成为一名独立的调查员至关重要。埃默里大学的实验室、临床设施和学术环境将为Fitzpatrick博士提供理想的环境，以研究氧化应激、AM成熟和功能对严重哮喘儿童的生物学和临床影响。通过与实验室科学导师(卢·安·布朗博士)、临床儿科哮喘专家(W·杰拉尔德·蒂格博士)以及由经验丰富的科学和临床研究人员组成的广泛网络的合作，菲茨帕特里克博士将获得发展独立学术研究事业的基础。严重哮喘是儿童发病率的一个重要来源。虽然严重哮喘的发病机制尚不清楚，但症状被认为是持续的呼吸道炎症造成的，呼吸道感染是主要触发因素。严重哮喘与呼吸道感染风险之间的确切联系机制尚未明确。菲茨帕特里克博士此前曾证明，患有严重哮喘的儿童AM功能受损，这种功能可以通过补充抗氧化剂(谷胱甘肽)来恢复。这些数据表明，在患有严重哮喘的儿童中，呼吸道氧化应激可能直接抑制AM功能，这一发现可能解释了该人群呼吸道感染风险增加的原因。这一建议将检验一种假说，即严重的哮喘引起的炎症和氧化应激通过损害AM巨噬细胞的成熟而导致AM功能受损。将测试三个目标：1)重症哮喘儿童是否存在影响AM成熟的呼吸道炎症和氧化应激；2)抗炎药罗格列酮是否能恢复AM成熟和功能；3)重症哮喘儿童AM功能受损是否预示呼吸道感染和症状控制不良。这项建议的结果可能会影响患者护理和临床评估，并将为儿童严重哮喘的病理生理学提供更多的洞察力。这一提议将为进一步的研究奠定基础，所确定的机制最终可能成为未来干预试验的目标。

DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and bench laboratory skills of Dr. Anne Fitzpatrick so that she may become an independent investigator with expertise in clinical translational research. Dr. Fitzpatrick's long-term goal is to identify novel biological mechanisms responsible for severe asthma in children. Steps integral to the attainment of this goal are: 1) to acquire the necessary bench laboratory skills that will enable her to conduct independent clinical translational experiments; and 2) to engage in multidisciplinary mechanistic studies of oxidant stress and alveolar macrophage (AM) function in children with asthma. This Research Career Award will allow Dr. Fitzpatrick to not only develops her research skills and expertise, but also to pursue a didactic phase of study, which is essential for her development into an independent investigator. The laboratories, clinical facilities, and academic environment at Emory University will provide Dr. Fitzpatrick with the ideal setting to investigate the biological and clinical impact of oxidant stress and AM maturation and function in children with severe asthma. Through collaboration with a laboratory science mentor (Dr. Lou Ann Brown), a clinical pediatric asthma specialist (Dr. W. Gerald Teague), and an extensive network of experienced scientific and clinical researchers, Dr. Fitzpatrick will obtain the foundation for the development of an independent academic research career. Severe asthma is a significant source of morbidity in children. Although the pathogenesis of severe asthma is unclear, symptoms are thought to result from persistent airway inflammation, with respiratory infections as a major trigger. The exact mechanisms linking severe asthma and the risk of respiratory infection are not well defined. Dr. Fitzpatrick has previously demonstrated that children with severe asthma have impaired AM function, which is restored with antioxidant (glutathione) supplementation. These data suggest that airway oxidative stress may directly inhibit AM function in children with severe asthma, a finding which may account for the increased risk of respiratory infection in this population. This proposal will test the hypothesis that severe asthma-induced inflammation and oxidant stress result in compromised AM function via impairment of AM macrophage maturation. Three aims will be tested: 1) whether children with severe asthma have airway inflammation and oxidant stress, which impair AM maturation; 2) whether AM maturation and function will be restored with the anti-inflammatory agent rosiglitizone; and 3) whether impaired AM function predicts respiratory infection and poor symptom control in children with severe asthma. The outcome of this proposal may impact patient care and clinical assessment, and will offer greater insight into the pathophysiology of severe asthma in children. This proposal will lay the foundation for further studies, and the mechanisms identified may ultimately be targeted in future interventional trials.