The role of neuropilin-2 in regulating environmental airways injury

项目摘要/摘要 本次K08临床科学家导师职业发展奖申请的总体目标是 为莫兰医生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包含严格研究内容的训练计划 通过教学指导，建立成功职业生涯所必需的思维过程和原则 发展。有了在这项提议中获得的知识和培训，莫兰博士将处于有利地位 对环境介导性肺部疾病的机制进行创新性的翻译研究。 内毒素(内毒素，LPS)和臭氧是常见的空气污染物，会造成显著的 呼吸系统疾病的发病率和死亡率。肺天然免疫细胞，包括肺泡巨噬细胞(AM)， 在介导吸入内毒素和臭氧的炎症反应中发挥关键作用。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， 仍然没有定义。莫兰博士最近报道，神经毛细蛋白-2(NRP2)-一种具有多种功能的蛋白质， 膜结合型和可溶性异构体--由人和小鼠AM在脂多糖刺激后上调。 有趣的是，髓系特异性消融NRP2增加了内毒素诱导的呼吸道炎症，表明 NRP2负向调节肺部的炎症反应。此外，初步研究表明， 臭氧暴露增加小鼠肺中NRP2的表达，提示NRP2的上调可能是一种 对吸入环境污染物的一般抗炎反应。对于这项提议，莫兰博士将 探讨NRP2负性调节污染物介导的呼吸道炎症的机制。在……里面 目的1，他将确定膜结合的NRP2是否直接抑制内毒素和臭氧介导的激活 人和小鼠AM在目标2中，他将确定一种可溶的NRP2亚型是否能减弱内毒素-和臭氧- 诱导小鼠呼吸道炎症。在目标3中，他将开始将他的发现转化为人类，通过确定 吸入脂多糖对健康志愿者痰和血清NRP2水平的影响这些研究将是 首先研究NRP2在污染物引发的呼吸道炎症中的免疫调节作用，并可能 揭示环境呼吸道损伤的新治疗靶点和/或生物标志物。

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.