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: 10542437
• 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/10542437
• 关键词: Address; Affect; Agonist; Airway Disease; Area; Asthma; Award; 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 Cells; Epithelial Physiology; Epithelium; 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; Knock-out; 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; Sorting; 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; biomarker validation; 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.

项目总结