Modulating macrophage-mediated Inflammation in cystic fibrosis

摘要 博士凯瑟琳希塞特的研究重点是了解巨噬细胞在慢性炎症中的作用。 炎症性肺病她的长期目标是成为一名独立的医生科学家 从事临床实践和转化研究，重点是囊性疾病 纤维化（CF）。为了实现这一目标，Hisert博士定义了一个全面的职业发展 该计划建立在她之前在基础免疫学研究方面的培训基础上，包括继续 她在UW成人CF诊所的临床技能的发展，并在计算指令 分析“组学”技术产生的大型数据集的技能。此次培训将使 成功执行拟议的研究，并为Hisert博士的职业生涯做好准备， 可以进行真正的临床研究 这项研究计划调查了一种新型抗炎药物的潜在用途， 硝酸镓，通过抑制促炎性巨噬细胞来改善疾病结局 应答在之前的1b期临床试验中，镓改善了CF患者的肺功能， 慢性细菌性呼吸道感染，但镓的治疗效果是否是由于其抗- 微生物特性或抗炎特性尚不清楚。希塞特博士将测试 假设镓通过抑制前炎症因子减少LPS和细菌介导的肺损伤， 炎性巨噬细胞功能，并减少CF患者的气道炎症， 慢性感染目标1将确定镓改变了哪些巨噬细胞功能， 研究镓减轻巨噬细胞炎症的分子机制 应答目标2将使用小鼠模型来测试镓是否可以保护LPS介导的肺 通过抑制体内促炎性巨噬细胞反应来减轻损伤。目标3将采取 II期临床试验的优势，测试IV镓改善CF肺功能的能力 慢性假单胞菌感染的患者。希塞特医生会从痰中分离出巨噬细胞 在患者接受IV镓之前和之后，并调查是否抑制巨噬细胞 促炎基因表达与改善的肺功能有关。综合这些 研究将导致更好地了解镓的抗炎作用，并探索 抑制促炎性巨噬细胞功能在CF中可能是治疗性的， 以及可能的其他慢性炎症性疾病。

ABSTRACT Dr. Katherine Hisert's research is focused on understanding the role of macrophages in chronic inflammatory lung diseases. Her long term goal is to become an independent physician scientist engaged in clinical practice and translational research, with a focus on the disease cystic fibrosis (CF). To achieve this goal, Dr. Hisert has defined a comprehensive career development program that builds on her prior training in basic immunology research, including continued development of her clinical skills in the UW Adult CF clinic, and instruction in computational skills for analysis of large datasets generated by “omics” technologies. This training will enable successful execution of the proposed studies, and prepare Dr. Hisert for a career in which she can perform true bench to bedside research. This research proposal investigates the potential use of a novel anti-inflammatory medication, gallium nitrate, to improve disease outcomes by suppressing pro-inflammatory macrophage responses. In a prior phase 1b clinical trial, gallium improved lung function in CF patients with chronic bacterial airway infections, but whether gallium's therapeutic effect was due to its anti- microbial properties or to anti-inflammatory properties was unclear. Dr. Hisert will test the hypothesis that gallium reduces LPS- and bacterially mediated lung injury by suppressing pro- inflammatory macrophage functions, and decreases airway inflammation in CF patients with chronic infections. Aim 1 will determine which macrophage functions are altered by gallium, and investigate the molecular mechanisms by which gallium attenuates macrophage inflammatory responses. Aim 2 will use murine models to test if gallium protects against LPS-mediated lung injury by suppressing pro-inflammatory macrophage responses in vivo. Aim 3 will take advantage of a phase II clinical trial testing IV gallium's ability to improve lung function in CF patients with chronic Pseudomonas infections. Dr. Hisert will isolate sputum macrophages before and after patients receive IV gallium and investigate whether suppression of macrophage pro-inflammatory gene expression is associated with improved lung function. Together these studies will lead to a better understanding of gallium's anti-inflammatory effects, and explore the possibility that suppressing pro-inflammatory macrophage functions could be therapeutic in CF, and possibly other chronic inflammatory diseases.