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

半胱氨酰白三烯 E4 受体 GPR99 协调气道上皮细胞分化和 2 型肺部炎症

• 批准号: 9371062
• 负责人: Lora Bankova
• 金额: $ 19.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371062
• 关键词: Affinity; Allergens; Allergic Disease; Alternaria; Aspirin; Asthma; Automobile Driving; Award; Basophils; Bioinformatics; Biology; Breathing; Bronchoconstriction; Brush Cell; Cell Count; Cell Differentiation process; Cell physiology; Cells; Complement; Data; Development; Development Plans; Disease; Environment; Eosinophilia; Epithelial; Epithelial Cells; Event; Five-Year Plans; Funding; Future; Generations; Genes; Genetic Transcription; Genomics; Goals; Goblet Cells; Grant; Hospitals; Human; Hypersensitivity; Imaging Techniques; Immune; Immunity; Immunology; Inflammation; Inflammatory Response; Interleukin-13; Intestines; Knowledge; Laboratories; Lead; Leadership; Leukotriene E4; Light; Liquid substance; Lung; Lung Inflammation; Lymphoid Cell; Mediating; Mediator of activation protein; Mentorship; Metaplasia; Methods; Modeling; Molds; Molecular; Mucins; Mucous Membrane; Mus; Nose; Obstruction; Patients; Pharmacology; Physicians; Population; Positioning Attribute; Process; Production; Pulmonary Inflammation; Recruitment Activity; Reporter; Reporting; Research; Research Personnel; Resistance; Resources; Role; Scientist; Secure; Severities; Signal Transduction; Source; Structure of mucous membrane of nose; Surface; Systems Biology; TSLP gene; Techniques; Testing; Therapeutic; Time; Tissues; Training; Translational Research; United States National Institutes of Health; Up-Regulation; Update; Virus; Woman; Work; Writing; airborne allergen; airway inflammation; airway remodeling; aspirin-exacerbated respiratory disease; career; career development; cell type; curriculum development; cysteinyl-leukotriene; didactic education; disorder control; eosinophil; feeding; gut microbiota; inhibitor/antagonist; mast cell; mucosal site; novel; profiles in patients; receptor; research and development; respiratory; response; responsible research conduct; skills; transcription factor; transcriptome; transcriptome sequencing; translational research program

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.

项目概要/摘要： 该提案详细介绍了一个五年计划，旨在为候选人 Lora Bankova 医学博士提供以下知识 和专业知识，成为过敏和免疫学领域的独立研究者。这 研究重点是稳定的半胱氨酰白三烯 (cysLT) 代谢物以前未被认识到的作用 LTE4 控制近端事件，导致对户外霉菌产生 2 型免疫力 空气过敏原，链格孢属。结合使用细胞和分子方法，候选人将 检验 GPR99 通过以下途径驱动先天 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 LTE4 是唯一稳定的 cysLT 代谢物并且 在过敏原、病毒、阿司匹林引起的哮喘中检测到，具有重大的转化意义 用于哮喘。本次 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。 Bankova博士的长期目标是开发独立的转化研究项目 研究过敏性疾病的先天免疫控制。在支持期间，候选人将 通过教学课程补充她的实验室技能，以培养新兴基因的技能 测序和编辑方法、生物信息学和系统生物学课程、资助写作、 领导力，以及负责任地进行与应用密切相关的研究。这将有助于 她在获奖的第三年和第四年过渡到独立。班科娃博士将会工作 在 cysLT 生物学专家 Nora Barrett 医学博士和 Joshua Boyce 医学博士的指导下 炎症机制。 Bankova博士还组建了一支由杰出科学家组成的团队， 包括博士。金冈吉英、卡拉·金、布鲁斯·利维、霍华德·卡茨和 K·弗兰克·奥斯汀 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，在布里格姆医学院理想的科学环境中 妇女医院、免疫学培训、教学课程和职业发展计划将 使候选人能够获得独立的 NIH 资助并确立自己的医生地位 科学家专注于肥大细胞和 cysLT 在指导上皮细胞激活中的作用 粘膜表面的免疫偏向。