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: 10055030
• 负责人: ALIX ASHARE
• 金额: $ 11.12万
• 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/10055030
• 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Ashare博士花费额外的25%， 时间指导初级医生科学家在以患者为导向的研究炎症肺 疾病这个K24将为Ashare博士提供机会，扩大她在患者方面的项目- 以转化研究为导向，将新的医生科学家和博士科学家融入她的研究中， 研究计划，并允许额外的保护时间，使她可以指导更多的学员。 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提高 自己的指导技能。该K24描述了两个目标，涉及面向患者的翻译 使用从人类受试者获得的原代肺巨噬细胞的研究。每个目标都将服务于 作为新学员的个人项目。aim 1利用了巨噬细胞 从肺的不同区域分离的药物在代谢上是不同的， 研究肺上叶巨噬细胞糖酵解代谢增加对 炎症的产生。这一目标也将确定琥珀酸积累在 巨噬细胞炎症反应的产生。根据我们的数据显示 铜绿假单胞菌分离株中存在表型和基因型差异， 目的2将检验以下假设： 分离株差异性地刺激肺巨噬细胞免疫应答，并表现出不同的 对细胞外琥珀酸的反应。这两个独立但互补的目标将使 新的学员追求翻译病人为导向的研究项目，这将导致更大的 了解CF肺中的宿主-病原体相互作用。