Effect of Rhinovirus on airway epithelial reciprocal pathways influence NK cells.

该提案概述了一个为期五年的职业发展计划，旨在为Koff博士的职业生涯做好准备， 他是一位肺部医学领域的学术型医生兼科学家。Koff博士有兴趣研究气道上皮先天性 对呼吸道病毒的免疫反应。这种兴趣源于鼻病毒（RV）感染 是慢性气道疾病恶化的原因。到目前为止，没有有效的治疗方法， 急性加重存在，因此研究新的病毒机制对于有效的抗病毒治疗将是重要的。 博士Koff一直在研究气道上皮对RV等病原体的先天免疫反应， 已经集中在促炎级联反应，激活上皮表面受体[表皮生长 因子受体（EGFR）]通过产生IL-8/CXCL 8和抗病毒级联反应募集中性粒细胞 产生IP-10/CXCL 10以招募自然杀伤（NK）细胞，即靶向并杀死 病毒感染的细胞Koff博士建议检验以下假设：（1）RV启动EGFR和IP-10 气道上皮中的通路，其具有共同的起源但不同的下游信号;（2）这些 途径是相互的，两者之间的平衡决定了某些细胞的结果;（3）NK 由IP-10募集的细胞靶向并杀死RV感染的气道上皮。成熟的技术， 包括ELISA、流式细胞术、RT-PCR、免疫印迹和siRNA。Koff博士的导师Jay博士 Nadel和共同导师刘易斯拉尼尔博士是富有成效和资金充足的科学家，他们在气道方面具有专业知识 上皮细胞生物学和NK细胞免疫学，具有出色的培训成功记录 学术医生Koff博士已经组建了一个专家科学顾问委员会， 研究并帮助实施一项教育计划，以丰富他的发展。心血管 研究所和加州大学旧金山分校弗朗西斯科致力于发展学术 Koff博士的职业生涯，在资助期结束时，Koff博士将有能力开始职业生涯， 一位独立的研究者专注于结合肺细胞生物学和免疫学来了解 气道上皮对病毒感染的天然免疫应答机制。 相关性（参见说明）： 除了引起普通感冒外，鼻病毒还负责引起慢性炎症的恶化。 呼吸道疾病（如哮喘）。然而，迄今为止，没有有效的疗法来治疗这些疾病。 加重该建议将研究气道上皮对以下反应的信号通路： 鼻病毒感染和新机制的发现可能为未来的治疗提供靶点。

This proposal outlines a five-year career development program designed to prepare Dr. Koff for a career as an academic physician-scientist in pulmonary medicine. Dr. Koff is interested to study airway epithelial innate immune responses to respiratory viruses. This interest arose from knowledge that Rhinovirus (RV) infections are responsible for exacerbations of chronic airway diseases. To date, no effective therapy for these exacerbations exists, so investigating novel viral mechanisms will be important for effective antiviral therapy. Dr. Koff has been examining airway epithelial innate immune responses to pathogens such as RV, and he has focused on a pro-inflammatory cascade that activates an epithelial surface receptor [epidermal growth factor receptor (EGFR)] to recruit neutrophils via the production of IL-8/CXCL8, and an anti-viral cascade that produces IP-10/CXCL10 to recruit natural killer (NK) cells, specialized lymphocytes that target and kill virus-infected cells. Dr. Koff proposes to test the hypotheses that: (1) RV initiates both EGFR and IP-10 pathways in airway epithelium, which have a common origin but divergent downstream signals; (2) these pathways are reciprocal, and the balance between the two determines certain cell outcomes; and (3) NK cells, recruited by IP-10, target and kill RV-infected airway epithelium. Well established techniques that include ELISA, flow cytometry, RT-PCR, immunoblot, and siRNA will be used. Dr. Koff's mentor, Dr. Jay Nadel, and co-mentor, Dr. Lewis Lanier, are productive and well-funded scientists with expertise in airway epithelial cell biology and NK cell immunology with outstanding track records for training successful academic physicians. Dr. Koff has assembled an expert scientific advisory committee who will oversee his research and help implement an educational plan that will enrich his development. The Cardiovascular Research Institute and the University of California, San Francisco are committed to developing the academic career of Dr. Koff, and at the end of the grant period, Dr. Koff will be well equipped to embark on a career as an independent investigator focused on combining pulmonary cellular biology and immunology to understand the mechanisms of airway epithelial innate immune responses to viral infection. RELEVANCE (See instructions): In addition to causing the common cold, Rhinovirus is responsible for causing exacerbations of chronic airway diseases (e.g. asthma). However, to date there are no effective therapies to treat these exacerbations. This proposal will investigate the signaling pathways of airway epithelial responses to Rhinovirus infection, and the discovery of novel mechanisms may provide targets for future therapies.