Solitary Chemosensory Cell Regulation of Airway Inflammation and Repair

气道炎症和修复的孤立化学感应细胞调节

基本信息

批准号：
10320452
负责人：
Michael Aaron Kohanski
金额：
$ 16.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-20 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10320452
关键词：
Address Affect Agonist Airway Disease Area Asthma Award BMX gene Basal Cell Bioinformatics Biology Bone Marrow Brush Cell Calcium Signaling Cell Culture Techniques Cell Differentiation process Cell physiology Cells Complex Coupled Cyclic AMP Data Defensins Disease Epithelial Epithelial Cells Epithelial Physiology Flow Cytometry Foundations Funding GTP-Binding Proteins Gene Expression Gene Expression Profiling Genes Goals Head and Neck Surgery Helminths Histopathology Human Immunity Immunofluorescence Immunologic Immunology Inflammation Inflammatory Inflammatory Response Interleukin-13 Intestines Ion Channel Irrigation Knockout Mice Knowledge Lentivirus Ligands Mechanics Mediating Medical Membrane Mentors Mentorship Modeling Mouse Strains Mucosal Immune Responses Mucous Membrane Mus Nasal Polyps Nose Nose Diseases Observational Study Otolaryngology Paracrine Communication Pathway interactions Patients Pennsylvania Persons Phosphotransferases Physiological Processes Polyps Population Potassium Potassium Channel Property Proteins Protocols documentation Pyroglyphidae Regulation Research Research Personnel Resistance Role Sampling Sensory Signal Pathway Signal Transduction Sinus Stimulus Surgical Management TRPM5 gene Taste Buds Taste Perception Testing Tissues Tongue Trachea Training United States Universities Work X Chromosome airway inflammation airway repair antimicrobial peptide career channel blockers chronic rhinosinusitis clinical practice cohort epithelial repair experience experimental study immune function improved inflammatory marker injured insight interest medical attention medical schools multidisciplinary new therapeutic target novel paracrine patient subsets phenotypic biomarker phosphoric diester hydrolase professor rat Gnat3 protein repaired respiratory respiratory health response single-cell RNA sequencing skills small hairpin RNA taste transduction transcription factor transcriptome sequencing wound wound closure

项目摘要

Project Summary Dr. Michael Kohanski is an assistant professor in the Department of Otorhinolaryngology – Head and Neck Surgery at the Perelman School of Medicine at The University of Pennsylvania. His clinical practice is focused on the medical and surgical management of inflammatory sinus and nasal disorders to improve the upper respiratory health of his patients. Dr. Kohanski's recent research efforts led to the finding that rare taste receptor expressing cells, solitary chemosensory cells (SCCs), are significantly enriched in inflammatory sinus polyps. This work established a connection between chronic rhinosinusitis (CRS) seen in humans to the important finding that tuft cells (analogous chemosensory cells in the intestine) are crucial for regulating Type 2 immunity. With the support of this award, Dr. Kohanski will develop expertise in mucosal immunology, epithelial physiology and bioinformatics to study solitary chemosensory cell regulation of airway inflammation and repair. Dr. Kohanski will augment his fund of knowledge through course work on immunology, epithelial physiology and bioinformatics. He will acquire new research skills with focused mentoring and training from a multidisciplinary group of experienced researchers at the University of Pennsylvania with expertise in epithelial taste receptor biology, Type 2 inflammation and epithelial cell physiology and repair as well as bioinformatics. This proposal focuses on identifying and characterizing taste-specific or inflammatory-specific inputs that stimulate SCC differentiation as well as understanding the mechanisms by which solitary chemosensory cells can amplify inflammatory and innate mucosal responses. This is a novel area of research with little work to date characterizing the role or function of chemosensory cells directly in human upper respiratory inflammatory diseases such as CRS with nasal polyps. In Aim 1a, Dr. Kohanski will characterize SCC abundance and SCC- specific gene expression directly in chronic rhinosinusitis with nasal polyps and determine if SCC abundance correlates with phenotypic markers of airway inflammation in a cohort of patients with CRS. In Aim 1b, he will determine if taste or inflammatory input stimulate differentiation of human SCCs and if there are distinct human SCC subtypes. In Aim 1c, the PI will leverage initial RNAseq results to further study the mechanisms of SCC differentiation and epithelial repair. In Aim 2, Dr. Kohanski will test the hypothesis that SCC-mediated epithelial signaling occurs through two-pore potassium channels. In Aim 2a, he will utilize Ussing chambers to determine if inflammation or SCC abundance affects K2P channel function. In Aim 2b, he will use a house dust mite model of inflammation with mouse strains deficient in two-pore potassium channels or SCC taste transduction to determine if inflammation amplifies the ability of SCCs to regulate epithelial defensin release. Progression through these experiments coupled with expert mentorship and coursework will provide Dr. Kohanski with the foundation to become an independent investigator with a focus on epithelial chemosensory cell function and the resultant impact on the mucosal immune response and inflammatory airway disease.

项目概要 Michael Kohanski 博士是耳鼻喉头颈科助理教授他在宾夕法尼亚大学佩雷尔曼医学院从事临床实践。关于炎症性鼻窦和鼻部疾病的药物和手术治疗，以改善上颌骨科汉斯基博士最近对患者的呼吸系统健康进行了研究，发现了这种罕见的味道。受体表达细胞，孤立的化学感应细胞（SCC），在炎症窦中显着富集这项工作建立了人类慢性鼻窦炎 (CRS) 与息肉之间的联系。重要发现：簇细胞（肠道中的类似化学感应细胞）对于调节 2 型细胞至关重要在该奖项的支持下，Kohanski 博士将发展粘膜免疫学方面的专业知识，上皮生理学和生物信息学研究气道炎症的孤立化学感应细胞调节 Kohanski 博士将通过免疫学、上皮细胞学课程来扩充他的知识储备。他将从生理学和生物信息学中获得新的研究技能。宾夕法尼亚大学经验丰富的研究人员组成的多学科小组，具有上皮细胞方面的专业知识味觉受体生物学、2 型炎症和上皮细胞生理学和修复以及生物信息学。该提案的重点是识别和表征特定味道或特定炎症的输入，这些输入刺激鳞状细胞癌分化并了解孤立化学感应细胞的机制可以放大炎症和先天粘膜反应，这是一个新的研究领域，目前还没有什么工作要做。直接表征化学感应细胞在人类上呼吸道炎症中的作用或功能的数据在目标 1a 中，Kohanski 博士将描述 SCC 丰度和 SCC- 等疾病。直接在慢性鼻窦炎伴鼻息肉中特异性基因表达，并确定 SCC 丰度在目标 1b 中，他将与一组 CRS 患者的气道炎症表型标志物相关。确定味觉或炎症输入是否刺激人类鳞状细胞癌的分化，以及是否存在独特的人类鳞状细胞癌在目标 1c 中，PI 将利用初始 RNAseq 结果进一步研究 SCC 的机制。在目标 2 中，Kohanski 博士将检验 SCC 介导的上皮细胞的假设。信号通过双孔钾通道发生。在目标 2a 中，他将利用尤斯室来实现。确定炎症或 SCC 丰度是否影响 K2P 通道功能在目标 2b 中，他将使用房屋。缺乏双孔钾通道或 SCC 味觉的小鼠品系的尘螨炎症模型转导以确定炎症是否增强 SCC 调节上皮防御素释放的能力。通过这些实验的进展加上专家的指导和课程作业将为博士提供帮助。 Kohanski 奠定了成为一名专注于上皮化学感应的独立研究者的基础细胞功能及其对粘膜免疫反应和炎症性气道疾病的影响。