Defining the role of tuft cells in allergic airway disease

定义簇细胞在过敏性气道疾病中的作用

• 批准号: 10525701
• 负责人: Maya Kotas
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525701
• 关键词: Address; Adopted; Air; Airway Disease; Allergic; Allergic inflammation; Animal Model; Antiinflammatory Effect; Apical; Asthma; Biology; Bronchi; Cell Culture Techniques; Cells; Chronic; Communities; Cystic Fibrosis; Data; Dinoprostone; Disease; Edema; Effectiveness; Environment; Epithelial; Fluids and Secretions; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Goals; Grant; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Interleukin-13; Intestines; Knowledge; Liquid substance; Lung; Lymphoid Cell; Mediator of activation protein; Mentors; Molecular Target; Morbidity - disease rate; Movement; Mucociliary Clearance; Mucous body substance; Mus; Nasal Polyps; Nasopharynx; Organoids; Output; Pathology; Patients; Phenotype; Physicians; Physiological; Process; Production; Prostaglandin Production; Reaction; Regulation; Reporting; Research; Respiratory System; Role; Scientist; Secretory Cell; Sinus; Small Intestines; Specialized Epithelial Cell; Surface; Symptoms; Techniques; Testing; Tissues; Trachea; Training; Tumor-infiltrating immune cells; WFDC2 gene; airway epithelium; airway hyperresponsiveness; airway inflammation; airway surface liquid; allergic airway disease; allergic airway inflammation; antimicrobial peptide; asthmatic; behavior influence; cellular targeting; chronic rhinosinusitis; comparative; cytokine; design; experimental study; human subject; human tissue; immune function; immunoregulation; improved; in vivo; in vivo Model; meetings; mortality; mouse model; mucus hypersecretion; new therapeutic target; novel therapeutics; pulmonary function; receptor; respiratory challenge; respiratory colonization; response; role model; single cell sequencing; therapeutic target; tool; translational study

Project Summary/Abstract This proposal describes a 5-year plan to achieve the candidate’s goal of becoming an independent physician- scientist studying interactions between the airway epithelium and the type 2 immune system. With a comprehensive plan of coursework and hands-on training, guided by a skilled scientific advisory and mentoring team, and situated within the exceptional intellectual environment at UCSF, Dr. Kotas will utilize established, specialized tools and techniques from her mentor’s lab and become newly proficient in primary airway epithelial culture, translational studies using human tissues, and state-of-the-art transcriptional techniques. By the end of this project, she will possess a unique toolset that will differentiate her from her mentor and will have sufficient data to launch an independent research group while contributing new knowledge to the scientific community. The investigative purpose of this proposal is to elucidate how tuft cells—specialized epithelial cells with poorly understood function—influence the behavior of nearby epithelial and immune cells during chronic type 2 airway inflammation. As chronic allergic inflammation is the underlying cause of morbidity and mortality in millions of patients with diseases such as nasal polyps and type 2 high asthma, an improved understanding of the cells and molecules that contribute to these pathologies is needed to design new therapies. In preliminary data, Dr. Kotas finds that tuft cells in the chronically allergic upper airway environment adopt a distinct “allergic” phenotype characterized by increased production of prostaglandin E2 (PGE2). This is concurrent with a transcriptional signature of PGE2 on the neighboring epithelium, while in vitro, PGE2 stimulates epithelial fluid secretion. Transcriptional signatures of allergic tuft cells and PGE2 activation are also observed in the bronchus in type 2 high asthmatics, suggesting similar pathology throughout the allergically-inflamed respiratory tract. These findings urge further examination of tuft cells and tuft cell-derived PGE2 in allergic airway disease. In this proposal, Dr. Kotas will build upon her preliminary data to probe the effects of tuft cells and PGE2 on airway homeostasis. Aim 1 will use mouse cells in vitro and whole animal modeling in vivo to examine tuft cell- dependent alterations mucociliary movement and airway surface liquid composition. Aim 2 will examine the effects of tuft cells and PGE2 on the type 2 immune system in mouse models of allergic airway disease. And Aim 3 will return focus to human subjects and determine the phenotype and activation state of tuft cells in the lower airway in type 2 high asthma. Together, the proposed experiments will improve our fundamental understanding of how tuft cells contribute to allergic airway disease, and may identify new molecular and cellular targets for future therapy.

项目总结/摘要 该提案描述了一个5年计划，以实现候选人成为独立医生的目标- 研究呼吸道上皮细胞和2型免疫系统之间相互作用的科学家。与 全面的课程和实践培训计划，由熟练的科学咨询和指导指导 团队，并在加州大学旧金山分校特殊的智力环境中，博士Kandy将利用建立， 专业的工具和技术，从她的导师的实验室，并成为新的精通初级气道上皮 培养、使用人类组织的翻译研究和最先进的转录技术。年底前 在这个项目中，她将拥有一个独特的工具集，这将使她与她的导师区分开来，并将有足够的 数据，以启动一个独立的研究小组，同时为科学界贡献新的知识。 这项建议的研究目的是阐明簇状细胞-特化的上皮细胞如何与弱分化的上皮细胞结合， 了解慢性2型气道疾病期间附近上皮细胞和免疫细胞的功能-影响行为 炎症由于慢性过敏性炎症是数百万人发病和死亡的根本原因， 患有鼻息肉和2型高哮喘等疾病的患者，对细胞的了解有所提高， 需要有助于这些病理的分子来设计新的疗法。根据初步数据， 发现在慢性过敏性上呼吸道环境中的毛簇细胞具有明显的“过敏性”表型 其特征在于前列腺素E2（PGE 2）的产生增加。这是与转录同时发生的。 PGE 2在邻近上皮上的特征，而在体外，PGE 2刺激上皮液体分泌。 在2型哮喘患者的支气管中也观察到过敏性簇细胞和PGE 2活化的转录特征。 高度哮喘患者，这表明在过敏性炎症的呼吸道中存在类似的病理学。这些 这些发现促使进一步研究过敏性气道疾病中的簇状细胞和簇状细胞衍生的PGE 2。 在这项提案中，Kendy博士将以她的初步数据为基础，探索簇状细胞和PGE 2对 气道稳态目的1将利用体外培养的小鼠细胞和体内的整体动物模型， 依赖性改变粘膜纤毛运动和气道表面液体组成。目标2将审查 在过敏性气道疾病小鼠模型中，簇状细胞和PGE 2对2型免疫系统的影响。和 Aim 3将把焦点回到人类受试者身上，并确定在人类中簇状细胞的表型和激活状态。 2型高度哮喘的下气道。总之，拟议的实验将改善我们的基本 了解簇状细胞如何促进过敏性气道疾病，并可能识别新的分子和细胞 未来治疗的目标。