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

描述(由申请人提供)：这份建议书概述了一个为期五年的职业发展计划，旨在为科夫博士作为一名肺部医学学术内科科学家的职业生涯做好准备。科夫博士感兴趣的是研究呼吸道上皮细胞对呼吸道病毒的先天免疫反应。这种兴趣源于对鼻病毒(RV)感染导致慢性呼吸道疾病恶化的了解。到目前为止，还没有针对这些恶化的有效治疗方法，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。科夫博士一直在研究呼吸道上皮细胞对轮状病毒等病原体的先天免疫反应，他一直专注于一个促炎级联反应，它激活上皮表面受体[表皮生长因子受体(EGFR)]，通过产生IL-8/CXCL8来招募中性粒细胞，以及一个抗病毒级联反应，产生IP-10/CXCL10来招募自然杀伤(NK)细胞，这是一种针对并杀死病毒感染细胞的特殊淋巴细胞。Koff博士建议检验假设：(1)RV在呼吸道上皮中同时启动EGFR和IP-10通路，这两个通路具有共同的起源，但下游信号不同；(2)这些通路是相互的，两者之间的平衡决定了某些细胞结果；以及(3)由IP-10招募的NK细胞，靶向并杀死RV感染的呼吸道上皮。将使用成熟的技术，包括ELISA、流式细胞术、RT-PCR、免疫印迹和siRNA。科夫博士的导师杰伊·纳德尔博士和共同导师刘易斯·拉尼尔博士都是多产且资金雄厚的科学家，他们在呼吸道上皮细胞生物学和NK细胞免疫学方面拥有专业知识，在培养成功的学术医生方面有着出色的记录。科夫博士已经组建了一个专家科学顾问委员会，该委员会将监督他的研究，并帮助实施一项教育计划，这将丰富他的发展。心血管研究所和加州大学旧金山分校致力于发展Koff博士的学术生涯，在资助期结束时，Koff博士将成为一名独立研究员，专注于将肺细胞生物学和免疫学相结合，以了解呼吸道上皮细胞对病毒感染的先天免疫反应的机制。 除了导致普通感冒外，鼻病毒还导致慢性呼吸道疾病(如哮喘)的恶化。然而，到目前为止，还没有有效的治疗方法来治疗这些恶化。这项建议将研究呼吸道上皮细胞对鼻病毒感染的信号通路，新机制的发现可能为未来的治疗提供靶点。

DESCRIPTION (provided by applicant): 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. 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.