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

描述（由申请人提供）：该提案概述了一个为期五年的职业发展计划，旨在使Koff博士成为肺病医学的学术医师和科学家。Koff博士感兴趣的是研究呼吸道病毒对气道上皮的先天免疫反应。这种兴趣源于人们对鼻病毒（RV）感染可导致慢性气道疾病恶化的认识。到目前为止，还没有有效的治疗这些恶化的方法，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。Koff博士一直在研究气道上皮对RV等病原体的先天免疫反应，他关注的是促炎级联反应，该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/CXCL8来招募中性粒细胞，以及抗病毒级联反应，产生IP-10/CXCL10来招募自然杀伤细胞（NK）， NK细胞是专门针对并杀死病毒感染细胞的淋巴细胞。Koff博士建议验证以下假设：(1)RV启动气道上皮中的EGFR和IP-10通路，它们具有共同的起源，但下游信号不同；(2)这些途径是相互作用的，两者之间的平衡决定了一定的细胞结果；(3)由IP-10募集的NK细胞靶向并杀死rv感染的气道上皮。将使用包括ELISA、流式细胞术、RT-PCR、免疫印迹和siRNA在内的成熟技术。Koff博士的导师Jay Nadel博士和联合导师Lewis Lanier博士是富有成效和资金充足的科学家，他们在气道上皮细胞生物学和NK细胞免疫学方面具有专业知识，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，他们将监督他的研究，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的研究者，专注于将肺细胞生物学和免疫学相结合，以了解气道上皮对病毒感染的先天免疫反应机制。

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.