The role of neuropilin-2 in regulating environmental airways injury

Neuropilin-2在调节环境气道损伤中的作用

• 批准号: 9927638
• 负责人: Timothy Moran
• 金额: $ 21.17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927638
• 关键词: Ablation; Advisory Committees; Air Pollution; Alveolar Macrophages; Animal Model; Anti-Inflammatory Agents; Attenuated; Binding; Biological; Biological Markers; Bronchoalveolar Lavage Fluid; Cells; Clinical; Data; Development; Endotoxins; Environment; Environmental Pollutants; Exposure to; Flow Cytometry; Funding; Genes; Goals; Human; Immune; Immune signaling; Immunology; In Vitro; Inflammatory Response; Inhalation; Innate Immune Response; Instruction; K-Series Research Career Programs; Knock-out; Knowledge; Learning; Ligands; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Macrophage Activation; Measures; Mediating; Mediator of activation protein; Membrane; Mentors; Morbidity - disease rate; Mus; Myelogenous; Natural Immunity; Neuropilin-2; Ozone; Pathway Analysis; Physicians; Play; Positioning Attribute; Prevention; Principal Investigator; Process; Production; Protein Isoforms; Proteins; Recombinants; Reporting; Research; Respiratory System; Role; Scientist; Semaphorins; Serum; Signal Transduction; Small Interfering RNA; Sputum; Techniques; Testing; Tissues; Training; Translating; Translational Research; Up-Regulation; Vascular Endothelial Growth Factors; airway inflammation; career; career development; cytokine; design; environmental agent; healthy volunteer; immunoregulation; in vivo; inflammatory lung disease; injured airway; innovation; knock-down; learning strategy; lung injury; macrophage; mortality; neutrophil; new therapeutic target; overexpression; ozone exposure; pollutant; prevent; receptor; skills; skills training; therapeutic biomarker; translational study

PROJECT SUMMARY/ABSTRACT The overall objective of this K08 Mentored Clinical Scientist Career Development Award Application is to provide Dr. Moran with the essential skills and training necessary to become an independent physician scientist. Dr. Moran and his mentor have designed a training plan with a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. With the knowledge and training acquired during this proposal, Dr. Moran will be well positioned to conduct innovative translational studies into the mechanisms of environment-mediated lung diseases. Endotoxin (lipopolysaccharide, LPS) and ozone are common airborne pollutants that cause significant respiratory disease morbidity and mortality. Lung innate immune cells, including alveolar macrophage (AM), play a critical role in mediating inflammatory responses to inhaled endotoxin and ozone. The key molecules that regulate innate immune responses to inhaled pollutants, and thus prevent pollutant-induced lung injury, remain undefined. Dr. Moran has recently reported that neuropilin-2 (NRP2)—a pleiotropic protein with membrane-bound and soluble isoforms—is upregulated by human and murine AM following LPS stimulation. Interestingly, myeloid-specific ablation of NRP2 augments LPS-induced airway inflammation, indicating that NRP2 negatively regulates inflammatory responses in the lungs. In addition, preliminary studies show that ozone exposure increases NRP2 expression in murine lungs, suggesting that upregulation of NRP2 may be a general anti-inflammatory response to inhaled environmental pollutants. For this proposal, Dr. Moran will investigate the mechanisms by which NRP2 negatively regulates pollutant-mediated airway inflammation. In Aim 1, he will determine if membrane-bound NRP2 directly inhibits LPS- and ozone-mediated activation of human and murine AM. In Aim 2, he will determine if a soluble isoform of NRP2 attenuates LPS- and ozone- induced airway inflammation in mice. In Aim 3, he will begin to translate his finding to humans by determining the effects of inhaled LPS on sputum and serum NRP2 levels in healthy volunteers. These studies will be the first to investigate the immunoregulatory role of NRP2 in pollutant-triggered airway inflammation, and may reveal a new therapeutic target and/or biomarker for environmental airways injury.

项目总结/摘要 K 08指导临床科学家职业发展奖申请的总体目标是 为莫兰博士提供成为一名独立医生所需的基本技能和培训 科学家莫兰博士和他的导师设计了一个培训计划，其中沿着了严格的研究内容 通过教学指导，建立成功职业生涯所需的思维过程和原则 发展凭借在此提案期间获得的知识和培训，莫兰博士将处于有利地位 对环境介导的肺部疾病的机制进行创新的转化研究。 内毒素（脂多糖，LPS）和臭氧是常见的空气污染物，其引起显著的 呼吸道疾病发病率和死亡率。肺固有免疫细胞，包括肺泡巨噬细胞（AM）， 在介导对吸入的内毒素和臭氧的炎症反应中起关键作用。的关键分子 调节对吸入污染物的先天免疫反应，从而防止污染物引起的肺损伤， 仍然未定义。Moran博士最近报道，神经纤毛蛋白-2（NRP 2）-一种多效性蛋白， 膜结合的和可溶的同种型-在LPS刺激后被人和鼠AM上调。 有趣的是，髓样特异性NRP 2消融增强了LPS诱导的气道炎症，表明 NRP 2负调节肺部的炎症反应。此外，初步研究表明， 臭氧暴露增加了小鼠肺中NRP 2的表达，这表明NRP 2的上调可能是 对吸入环境污染物的一般抗炎反应。对于这项提案，莫兰博士将 研究NRP 2负调节污染物介导的气道炎症的机制。在 目的1，他将确定膜结合的NRP 2是否直接抑制LPS和臭氧介导的活化。 人和鼠AM。在目标2中，他将确定NRP 2的可溶性同种型是否能减弱LPS和臭氧的作用。 诱导小鼠气道炎症。在目标3中，他将开始通过确定 吸入LPS对健康志愿者痰液和血清NRP 2水平的影响。这些研究将是 首先研究NRP 2在污染物引发的气道炎症中的免疫调节作用， 揭示了环境气道损伤的新的治疗靶点和/或生物标志物。