Modulating macrophage-mediated Inflammation in cystic fibrosis

调节囊性纤维化中巨噬细胞介导的炎症

• 批准号: 10371188
• 负责人: Katherine B Hisert
• 金额: $ 15.78万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371188
• 关键词: Adult; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Bacterial Infections; Cells; Chronic; Chronic Disease; Clinic; Clinical; Cystic Fibrosis; Cystic Fibrosis sputum; Data; Disease; Disease Outcome; Exhibits; Exposure to; Follow-Up Studies; Gallium; Gallium Nitrate; Gene Expression; Genes; Goals; Health; Human; Hypercalcemia; Immune; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Instruction; Knowledge; Lung; Measures; Mediating; Mentors; Molecular; Molecular Target; Mus; Nitric Oxide; Outcome; Pathology; Patient-Focused Outcomes; Patients; Persons; Phagocytosis; Pharmaceutical Preparations; Phase II Clinical Trials; Phase Ib Clinical Trial; Phenotype; Physicians; Production; Program Development; Property; Pseudomonas Infections; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Research; Research Proposals; Respiratory Failure; Respiratory Tract Infections; Role; Scientist; Sputum; Study Subject; Surface; Symptoms; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutic; Therapeutic Effect; Training; Translational Research; Work; acute infection; airway inflammation; antimicrobial; autoimmune inflammation; bench to bedside; career; career development; chromatin immunoprecipitation; chronic infection; chronic inflammatory disease; chronic inflammatory lung disease; clinical development; clinical practice; cystic fibrosis airway; cystic fibrosis patients; cytokine; human subject; improved; improved outcome; in vivo; iron metabolism; large datasets; lung injury; macrophage; mouse model; novel; pathogen; polarized cell; pulmonary function; reduce symptoms; response; skill acquisition; skills; transcription factor

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.

抽象的 Katherine Hisert博士的研究重点是了解巨噬细胞在慢性中的作用 她的长期目标是成为一名独立的物理科学家 从事临床实践和转化研究，重点是 纤维化（CF）。为了实现这一目标，Hisert博士定义了全面的职业发展 基于她先前在基本免疫学研究中培训的计划，包括继续 她在大学成人CF诊所的临床技能以及计算中的说明 通过“ OMICS”技术生成的大型数据集的分析技能。这项培训将使 成功地执行了拟议的研究，并为Hisert博士做好准备工作的职业 可以对床边研究进行真正的替补席。 该研究建议研究了一种新型抗炎药的潜在用途， 硝酸盐，通过抑制促炎性巨噬细胞来改善疾病预后 回答。在先前的1B临床试验中，CF患者的CF患者的肺功能提高了 慢性细菌气道感染，但甘油的治疗作用是否是由于其抗 微生物特性或抗炎特性尚不清楚。 Hisert博士将测试 假设包膜可通过抑制促进性来降低LPS和广泛介导的肺损伤 炎症性巨噬细胞功能，并减少CF患者的气道炎症 慢性感染。 AIM 1将确定哪些巨噬细胞函数被镀； 研究胆管减弱巨噬细胞炎症的分子机制 回答。 AIM 2将使用鼠模型测试镀仑是否可以防止LPS介导的肺 通过在体内抑制促炎性巨噬细胞反应来受伤。 AIM 3将采取 II期临床试验测试IV炮提高CF肺功能的能力的优势 患有慢性假单胞菌感染的患者。 Hisert博士将隔离痰巨噬细胞 在患者接受静脉注册之前和之后，研究巨噬细胞是否抑制 促炎基因表达与改善的肺功能有关。在一起 研究将使对甘油的抗炎作用有更好的了解，并探索 抑制促炎性巨噬细胞功能的可能性可能在CF中具有治疗性， 还有其他慢性炎症性疾病。