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 迈克尔·科汉斯基博士是耳鼻喉科的助理教授。 宾夕法尼亚大学佩雷尔曼医学院的外科手术。他的临床实践专注于 浅谈炎症性鼻窦及鼻部疾病的内外科治疗 他的病人的呼吸健康状况。科汉斯基博士最近的研究发现，罕见的味道 受体表达细胞，孤立性化学感觉细胞(Sccs)，在炎性鼻窦中显著丰富。 息肉。这项工作建立了人类慢性鼻窦炎(CRS)与 一项重要发现：绒毛细胞(肠道中类似的化学感觉细胞)对调节2型至关重要 豁免权。在这个奖项的支持下，科汉斯基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孤立性化学感觉细胞对呼吸道炎症的调节 并进行修复。Kohanski博士将通过免疫学、上皮学等课程来增加他的知识库 生理学和生物信息学。他将通过有重点的指导和培训获得新的研究技能 由宾夕法尼亚大学经验丰富的研究人员组成的多学科小组，拥有上皮细胞方面的专业知识 味觉感受器生物学、2型炎症和上皮细胞生理学和修复以及生物信息学。 该建议侧重于确定和表征特定口味或特定炎症的输入 刺激SCC分化，并了解孤立性化学感觉细胞 可以放大炎症和固有的粘膜反应。这是一个新的研究领域，几乎没有什么工作要做 化学感觉细胞在人类上呼吸道炎症中直接作用或功能的数据 慢性阻塞性肺疾病伴发鼻息肉。在目标1a中，Kohanski博士将描述SCC丰度和SCC- 慢性鼻窦炎鼻息肉中特异性基因的直接表达及SCC丰度的测定 与CRS患者队列中的呼吸道炎症表型标记物相关。在目标1b中，他将 确定味觉或炎性输入是否刺激人类干细胞分化，以及是否存在明显的人类 SCC子类型。在目标1c中，PI将利用初步的RNASEQ结果来进一步研究SCC的机制 分化和上皮修复。在目标2中，Kohanski博士将检验SCC介导的上皮细胞 信号通过两孔钾通道发生。在目标2a中，他将利用Ussing内庭 确定炎症或SCC丰度是否影响K2P通道功能。在目标2b中，他将使用一所房子 双孔钾通道或SCC味觉缺陷小鼠尘螨炎症模型的建立 转导以确定炎症是否增强了干细胞调节上皮防御素释放的能力。 通过这些实验的进展，再加上专家的指导和课程工作，将为Dr。 Kohanski与基金会合作，成为专注于上皮化学感觉的独立调查者 细胞功能及其对粘膜免疫反应和炎症性呼吸道疾病的影响。