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

项目总结/摘要： 该提案详细介绍了一个五年计划，为候选人Lora Bankova，MD提供知识， 和专业知识，成为过敏和免疫学领域的独立调查员。的 研究集中在稳定的半胱氨酰白三烯（cysLT）代谢物的先前未被认识的作用上 LTE 4在近端事件的控制导致2型免疫力的发展，以户外模具 空气过敏原，链格孢属。使用细胞和分子方法的组合，候选人将 测试GPR 99通过免疫系统驱动先天2型免疫和气道重塑的假设。 控制上皮细胞活化以产生IL-25。由于LTE 4是唯一稳定的cysLT代谢物， 在过敏原、病毒、阿司匹林引起的哮喘中检测到， 治疗哮喘这个K 08奖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 research. Bankova博士的长期目标是发展一个独立的转化研究计划 研究过敏性疾病的先天免疫控制在支持期间，候选人将 通过教学课程来补充她的实验室技能， 测序和编辑方法，生物信息学和系统生物学课程，资助写作， 领导，并负责进行研究密切相关的应用。这将有助于 她在获奖的第三和第四年向独立过渡。班科娃医生会 在诺拉巴雷特，医学博士和约书亚博伊斯，医学博士的指导下，cysLT生物学和 炎症机制。班科娃博士还组建了一个由杰出科学家组成的团队， 包括金冈义秀博士、卡拉·金、布鲁斯·利维、霍华德·卡茨和K.弗兰克·奥斯汀 他们投入了时间、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，在布里格姆的理想科学环境中， 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，以确保独立的国家卫生研究院的资金，并建立自己作为一个医生 一位专注于肥大细胞和cysLT在指导上皮细胞活化中的作用的科学家， 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.