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

基本信息

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
项目类别：
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

项目摘要

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。课程作业和实践培训的全面计划，以科学熟练的咨询和指导为指导 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。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症是导致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 Kotas 博士在初步数据中表示，设计新疗法需要促进这些病理的分子。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”表型其特征是前列腺素 E2 (PGE2) 的产生增加，这与转录同时发生。 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变化。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。目标 2 将检查粘液纤毛运动和气道表面液体成分的相关变化。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。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。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。