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.

项目摘要/摘要该建议描述了一项为期5年的计划，以实现候选人成为独立医生的目标 - 科学家研究气道上皮和2型免疫系统之间的相互作用。与在熟练的科学咨询和心理方面的指导下，课程工作和动手培训的全面计划团队，位于UCSF的杰出智力环境中，Kotas博士将利用，她的导师实验室的专业工具和技术，并新熟练精通主要气道上皮培养，使用人体组织的翻译研究以及最先进的转录技术。到结束这个项目，她将拥有一个独特的工具集，它将使她与她的心理区分开来，并将足够数据以启动一个独立的研究小组，同时向科学界贡献新知识。该提案的研究目的是阐明簇细胞如何 - 特定的上皮细胞较差可理解的齿功能 - 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造成发病率和死亡率的根本原因患有鼻息肉和2型高哮喘等疾病的患者，对细胞和细胞的了解得到了改善为了设计新疗法，需要有助于这些病理的分子。在初步数据中，Kotas博士发现长期过敏的上呼吸道环境中的簇细胞采用独特的“过敏”表型特征是前列腺素E2的产生增加（PGE2）。这与转录同时发生 PGE2在相邻上皮上的签名，而在体外，PGE2刺激上皮流体的分泌。在2型的支气管中也观察到过敏性簇细胞和PGE2激活的转录特征高哮喘患者，在整个过敏性呼吸道中表现出类似的病理。这些调查结果促使在过敏性气道疾病中进一步检查簇簇细胞和簇细胞衍生的PGE2。在此提案中，Kotas博士将建立在她的初步数据上，以探测簇细胞和PGE2对气道体内平衡。 AIM 1将在体内使用小鼠细胞在体外和整个动物建模中检查簇状细胞 - 依赖性改变的粘毛运动和气道表面液体组成。 AIM 2将检查簇状细胞和PGE2对过敏性气道疾病小鼠模型中2型免疫系统的影响。和 AIM 3将重点归因于人类受试者，并确定簇状细胞的表型和激活状态较低的2型高哮喘中的气道。拟议的实验将共同改善我们的基本了解簇细胞如何促进过敏性气道疾病，并可能鉴定出新的分子和细胞未来治疗的靶标。