Macrophage Pathogen Interactions in Regional Cystic Fibrosis Lung Inflammation

巨噬细胞病原体在局部囊性纤维化肺部炎症中的相互作用

• 批准号: 10207764
• 负责人: ALIX ASHARE
• 金额: $ 10.98万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207764
• 关键词: Advisory Committees; Award; Bronchiectasis; Cells; Clinical; Clinical Medicine; Clinical Research; Cystic Fibrosis; Data; Development; Disease; Doctor of Philosophy; Environment; Exhibits; Frequencies; Funding; Generations; Genotype; Glycolysis; Goals; Heterogeneity; Hypoxia; Immune; Immune response; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Junior Physician; Knowledge; Lead; Lobe; Lung; Lung Inflammation; Lung diseases; Mentors; Metabolic; Metabolism; Mission; Mucous body substance; Mutation; Pathogenesis; Phagocytosis; Phenotype; Physicians; Plug-in; Population; Production; Pseudomonas aeruginosa; Public Health; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Fibrosis; Research; Research Project Grants; Respiratory Failure; Role; Scientist; Succinates; Testing; Time; Translational Research; Translations; United States National Institutes of Health; Virulence; Virulence Factors; Work; adaptive immune response; base; chemokine; chronic infection; cystic fibrosis infection; cystic fibrosis patients; cytokine; extracellular; human disease; human subject; improved; inflammatory lung disease; innovation; lung lobe; lung upper lobe; macrophage; metabolic profile; microbiota; neutrophil; novel therapeutic intervention; pathogen; patient oriented; patient oriented research; pediatric patients; programs; recruit; regional difference; response; skills; time use; transcription factor

ABSTRACT The goal of this K24 is to provide support to allow Dr. Ashare to spend an additional 25% of her time mentoring junior physician scientists in patient-oriented research on inflammatory lung disease. This K24 will provide the opportunity for Dr. Ashare to expand her program in patient- oriented translational research, integrate new physician scientists and PhD scientists into her research program, and allow for additional protected time so she can mentor additional trainees. In addition, with the help of her senior advisory committee, she will also use this time to improve her own mentoring skills. This K24 describes two aims that involve patient-oriented translational research using primary lung macrophages obtained from human subjects. Each Aim will serve as an individual project for a new trainee. Aim1 exploits preliminary findings that macrophages isolated from different regions of the lung are metabolically different and will specifically investigate the impact of increased glycolytic metabolism in upper lobe macrophages on the generation of inflammation. This aim will also determine the role of succinate accumulation in the generation of the macrophage inflammatory response. Based upon our data demonstrating that there are phenotypic and genotypic differences in Pseudomonas aeruginosa isolates from different regions of the CF lung, Aim 2 will test the hypothesis that regional P. aeruginosa isolates differentially stimulate lung macrophage immune responses and exhibit different responses to extracellular succinate. These two independent but complementary aims will allow new trainees to pursue translational patient-oriented research projects that will lead to a greater understanding of host-pathogen interactions in the CF lung.

摘要 这个K24的目标是提供支持，让Share博士能够额外花费她25%的时间 时间指导初级内科科学家以患者为导向的肺炎性研究 疾病。这个K24将为Share博士提供机会，扩大她在患者- 面向转化性研究，将新的内科科学家和博士生纳入HER 研究计划，并留出额外的保护时间，这样她就可以指导更多的受训者。 此外，在她的高级顾问委员会的帮助下，她还将利用这段时间来提高 她自己的指导技能。这本K24描述了涉及以患者为中心的翻译的两个目标 使用从人类受试者获得的原代肺巨噬细胞的研究。每一个目标都会起作用 作为新学员的个人项目。Aim1利用初步发现巨噬细胞 从肺的不同区域分离出来的物质在新陈代谢上是不同的，并且会特异性地 探讨上叶巨噬细胞糖酵解代谢增强对血管生成的影响。 产生炎症。这一目标也将决定琥珀酸积累在 巨噬细胞炎症反应的产生。根据我们的数据显示 来自中国的铜绿假单胞菌存在表型和基因差异 Cf肺的不同区域，Aim 2将检验区域铜绿假单胞菌 分离株不同地刺激肺巨噬细胞免疫反应并表现出不同的 对胞外琥珀酸的反应。这两个独立但互补的目标将允许 新学员将从事面向患者的翻译研究项目，这将带来更大的 理解肺组织中宿主与病原体的相互作用。