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: 10701742
• 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/10701742
• 关键词: Address; Adopted; Air; Airway Disease; Allergic; Allergic inflammation; Animal Model; Antiinflammatory Effect; Apical; Asthma; Biology; Bronchi; Cell Culture Techniques; Cell secretion; Cells; Chronic; Communities; Curiosities; Cystic Fibrosis; Data; Dinoprostone; Disease; Edema; Effectiveness; Environment; Epithelial Cells; Epithelium; Fluids and Secretions; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Goals; Grant; Growth; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Interleukin-13; Intestines; Knowledge; Liquid substance; Lung; Lymphoid Cell; Mediator; Membrane; 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; Role; Scientist; Secretory Cell; Sensory; Sinus; Small Intestines; Specialized Epithelial Cell; Surface; Symptoms; Techniques; Testing; Tissues; Trachea; Training; 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 cell infiltrate; 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; skills; 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.

项目概要/摘要 该提案描述了实现候选人成为独立医生目标的 5 年计划 - 科学家研究气道上皮和 2 型免疫系统之间的相互作用。与一个 在熟练的科学咨询和指导的指导下，制定全面的课程作业和实践培训计划 Kotas 博士将利用加州大学旧金山分校 (UCSF) 的卓越智力环境，利用现有的、 导师实验室的专业工具和技术，并成为初级气道上皮新的熟练者 文化、利用人体组织的转化研究以及最先进的转录技术。到年底 在这个项目中，她将拥有一套独特的工具集，使她有别于她的导师，并且拥有足够的能力 数据来启动一个独立的研究小组，同时为科学界贡献新知识。 该提案的研究目的是阐明簇细胞（具有较差功能的特化上皮细胞）如何 了解功能——影响慢性 2 型气道期间附近上皮细胞和免疫细胞的行为 炎。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 型高度哮喘等疾病的患者，可以更好地了解细胞和 设计新疗法需要促进这些病理的分子。初步数据显示，Kotas 博士 发现慢性过敏性上呼吸道环境中的簇细胞采取独特的“过敏”表型 其特点是前列腺素 E2 (PGE2) 的产生增加。这与转录同时进行 PGE2 在邻近上皮上的特征，而在体外，PGE2 刺激上皮液分泌。 在 2 型支气管中也观察到过敏簇细胞的转录特征和 PGE2 激活 高哮喘患者，表明整个过敏性发炎的呼吸道有类似的病理学。这些 研究结果敦促进一步检查过敏性气道疾病中的簇细胞和簇细胞衍生的 PGE2。 在这项提案中，Kotas 博士将根据她的初步数据来探讨簇状细胞和 PGE2 对 气道稳态。目标 1 将使用体外小鼠细胞和体内整个动物模型来检查簇细胞 - 粘液纤毛运动和气道表面液体成分的相关改变。目标 2 将检查 簇细胞和 PGE2 对过敏性气道疾病小鼠模型 2 型免疫系统的影响。和 目标 3 将把焦点重新转移到人类受试者身上，并确定体内簇状细胞的表型和激活状态。 2 型高度哮喘的下呼吸道。总之，所提出的实验将改善我们的基础 了解簇细胞如何导致过敏性气道疾病，并可能识别新的分子和细胞 未来治疗的目标。