The Cysteinyl Leukotriene E4 Receptor, GPR99, Orchestrates Airway Epithelial Cell Differentiation and Type 2 Pulmonary Inflammation

项目摘要/摘要： 这项提案详细说明了一项五年计划，为候选人、医学博士洛拉·班科娃提供知识 和专业知识，成为过敏和免疫学领域的独立研究员。这个 研究集中在稳定的半胱氨酰白三烯(CysLT)代谢物以前未被认识到的作用上。 LTE4在控制导致对室外霉菌产生2型免疫的近端事件中的作用 空气过敏原，交链孢属。使用细胞和分子方法的组合，候选人将 测试GPR99通过GPR99驱动先天2型免疫和气道重塑的假设 控制上皮细胞激活以产生IL-25。由于LTE4是唯一稳定的cysLT代谢物和 在过敏原、病毒、阿司匹林引发的哮喘中被检测到，有显著的翻译意义 治疗哮喘。此K08奖项申请的短期目标是提供高级培训 成像技术、先进的基因组技术，包括RNA-Seq和人类翻译 研究。班科娃博士的长期目标是开发一个独立的翻译研究项目 研究过敏性疾病的先天免疫调控。在支持期间，候选人将 用授课课程补充她的实验室技能，以发展新兴基因的技能 测序和编辑方法，生物信息学和系统生物学的课程，拨款撰写， 领导力，以及与应用程序密切相关的负责任的研究行为。这将促进 她在获奖的第三年和第四年过渡到独立。班科娃医生会工作的 在医学博士诺拉·巴雷特和医学博士约书亚·博伊斯的指导下，CysLT生物学和 炎症的机制。班科娃博士还组建了一支杰出的科学家团队， 包括Kanaoka博士、Carla Kim博士、Bruce Levy博士、Howard Katz博士和K.Frank Austen博士， 投入了他们的时间、资源和专业知识来促进她的职业发展和研究 目标。在他们的指导和指导下，在布里格姆和 妇女医院、免疫学培训、教学课程和职业发展计划将 定位候选人以获得独立的NIH资金，并确立自己的医生地位 科学家专注于肥大细胞和CysLTs在指导上皮细胞激活中的作用 粘膜表面的免疫偏向。

PROJECT SUMMARY/ABSTRACT: This proposal details a five-year plan to provide the candidate, Lora Bankova, MD, with the knowledge and expertise to become an independent investigator in the field of Allergy and Immunology. The studies focus on a previously unrecognized role of the stable cysteinyl leukotriene (cysLT) metabolite LTE4 in the control of proximal events leading to development of type 2 immunity to the outdoor mold aeroallergen, Alternaria. Using a combination of cellular and molecular approaches, the candidate will test the hypothesis that GPR99 drives innate type 2 immunity and airway remodeling through the control of epithelial cell activation for IL-25 generation. As LTE4 is the only stable cysLT metabolite and is detected in asthma elicited by allergen, viruses, aspirin, there are significant translational implications for asthma. The short-term goals of this K08 award application are to provide training in advanced imaging techniques, advanced genomic techniques, including RNA-Seq, and human translational research. Dr. Bankova's long-term goal is to develop an independent translational research program studying the innate immune control of allergic disease. During the period of support the candidate will complement her laboratory skills with didactic coursework to develop skills in emerging gene sequencing and editing methods, courses in bioinformatics and systems biology, grant writing, leadership, and the responsible conduct of research germane to the application. This will then facilitate her transition to independence during the third and fourth years of the award. Dr. Bankova will work under the mentorship of Nora Barrett, MD and Joshua Boyce, MD, experts in cysLT biology and mechanisms of inflammation. Dr. Bankova has also assembled a team of extraordinary scientists, including Drs. Yoshihide Kanaoka, Carla Kim, Bruce Levy, Howard Katz, and K. Frank Austen, who have committed their time, resources, and expertise to facilitate her career development and research goals. Under their mentorship and guidance, in an ideal scientific environment at the Brigham and Women's Hospital, training in immunology, didactic curriculum, and career development plan will position the candidate to secure independent NIH funding and to establish herself as a physician scientist with a focus on the role of mast cells and cysLTs in instructing epithelial cell activation to guide immune bias at mucosal surfaces.