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

• 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
• 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

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.

项目摘要 Michael Kohanski博士是Otorhinolaryngology系的助理教授 - 头颈部 宾夕法尼亚大学佩雷​​尔曼医学院的手术。他的临床实践是集中的 关于炎症性鼻窦和鼻部疾病的医学和外科手术管理 患者的呼吸健康。 Kohanski博士最近的研究工作导致了这种稀有品味的发现 受体表达细胞，固体化学感应细胞（SCC）在炎症窦中显着富集 息肉。这项工作建立了人类中的慢性鼻孔炎（CRS）与 重要的发现，簇细胞（肠中的类似化学水敏细胞）对于调节2型至关重要 在该奖项的支持下，Kohanski博士将在粘膜免疫学方面发展专业知识， 上皮生理学和生物信息学研究气道注射的固体化学感应细胞调节 和维修。 Kohanski博士将通过免疫学课程，上皮来增强其知识基金 生理学和生物信息学。他将通过专注的心理和培训获得新的研究技能 宾夕法尼亚大学有经验的研究人员的多学科小组，具有上皮方面的专业知识 味觉受体生物学，2型炎症和上皮细胞生理学以及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特异性或炎症的投入 刺激SCC的分化以及了解固体化学感知细胞的机制 可以扩大炎症和先天的粘膜反应。这是一个新颖的研究领域，几乎没有工作 直接表征化学感应细胞在人上呼吸道炎症中的作用或功能的日期 诸如鼻息肉的CR等疾病。在AIM 1A中，Kohanski博士将表征SCC抽象和SCC- 特定的基因表达直接在慢性鼻塞炎中伴有鼻息肉，并确定SCC抽象是否是否 与CRS患者队列中气道注射的表型标记有关。在AIM 1B中，他会 确定味道或炎症输入是否刺激人类SCC的分化以及是否存在独特的人 SCC子类型。在AIM 1C中，PI将利用初始RNASEQ结果进一步研究SCC的机制 分化和上皮修复。在AIM 2中，Kohanski博士将测试SCC介导的上皮的假设 信号通过两孔的钾通道发生。在AIM 2A中，他将利用Ussing Chambers 确定炎症或SCC抽象是否影响K2P通道功能。在AIM 2B中，他将使用房屋 用小鼠菌株在两孔钾通道或SCC味道中缺乏小鼠菌株的粉尘小气丝模型 转导，以确定炎症放大器是否能够调节上皮防御素释放的能力。 通过这些实验的进步以及专家精神和课程的发展将为博士提供。 Kohanski拥有基础，成为一名独立研究者，重点是上皮化学感应 细胞功能以及对粘膜免疫反应和炎症气道疾病的影响。