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

这份提案概述了一项为期五年的职业发展计划，旨在为科夫博士的职业生涯做好准备 一位肺部医学方面的学术内科医生兼科学家。科夫博士对研究先天呼吸道上皮很感兴趣 对呼吸道病毒的免疫反应。这种兴趣源于对鼻病毒(RV)感染的了解 对慢性呼吸道疾病的恶化负有责任。到目前为止，还没有有效的治疗方法来治疗这些 病情恶化是存在的，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RV等病原体的先天免疫反应，他说 专注于激活上皮表面受体[表皮生长]的促炎级联反应 因子受体(EGFR)]通过产生IL-8/CXCL8来招募中性粒细胞，并通过抗病毒级联反应 它产生IP-10/CXCL10来招募自然杀伤(NK)细胞，这种特殊的淋巴细胞可以靶向并杀死 被病毒感染的细胞。科夫博士建议检验以下假设：(1)RV同时启动EGFR和IP-10 呼吸道上皮中具有共同起源但下游信号不同的通路；(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；以及(3)NK 被IP-10招募的细胞，靶向并杀死RV感染的呼吸道上皮细胞。成熟的技术， 包括酶联免疫吸附试验、流式细胞术、RT-PCR、免疫印迹和siRNA。科夫博士的导师，杰博士 纳德尔和共同导师刘易斯·拉尼尔博士都是多产的、资金雄厚的科学家，拥有呼吸道方面的专业知识 上皮细胞生物学和NK细胞免疫学，培训成功的杰出记录 学术内科医生。科夫博士组建了一个专家科学顾问委员会，该委员会将监督他的 研究并帮助实施教育计划，这将丰富他的发展。心血管疾病 研究院和加州大学旧金山分校致力于发展学术 科夫博士的职业生涯，在资助期结束时，科夫博士将做好准备，开始他的职业生涯 一位专注于将肺细胞生物学和免疫学相结合的独立研究人员 呼吸道上皮细胞对病毒感染的先天免疫反应机制。 相关性(请参阅说明)： 除了导致普通感冒外，鼻病毒还会导致慢性感冒的恶化 呼吸道疾病(如哮喘)。然而，到目前为止还没有有效的疗法来治疗这些疾病。 病情加重。这项建议将研究呼吸道上皮细胞对 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.