Solitary Chemosensory Cell Regulation of Airway Inflammation and Repair

项目摘要 博士Michael Kohanski是耳鼻咽喉-头颈部的助理教授 宾夕法尼亚大学佩雷尔曼医学院的外科医生。他的临床实践专注于 关于炎症性鼻窦和鼻部疾病的内科和外科治疗， 患者的呼吸系统健康。Kohanski博士最近的研究发现， 受体表达细胞，孤立的化学感受细胞（SCC），显着丰富的炎症窦 息肉这项工作建立了人类慢性鼻窦炎（CRS）与慢性鼻窦炎之间的联系。 一个重要的发现，簇状细胞（类似于肠道中的化学感受细胞）对调节2型糖尿病至关重要。 免疫力在该奖项的支持下，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单个化学感受细胞调节 和修复。Kohanski博士将通过免疫学、上皮细胞学和免疫学等课程来增加他的知识储备。 生理学和生物信息学。他将获得新的研究技能与重点指导和培训，从一个 宾夕法尼亚大学经验丰富的研究人员组成的多学科小组， 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。 该提案集中于识别和表征味道特异性或炎症特异性输入， 刺激SCC分化以及了解孤立的化学感受细胞 可以放大炎症和固有粘膜反应。这是一个新的研究领域， 直接表征化学感受细胞在人类上呼吸道炎症中的作用或功能的数据 鼻息肉的症状有哪些？在目标1a中，Kohanski博士将描述SCC丰度和SCC- 慢性鼻窦炎鼻息肉特异性基因表达及SCC丰度的测定 与CRS患者队列中气道炎症的表型标志物相关。在目标1b中，他将 确定味觉或炎症输入是否刺激人SCC的分化，以及是否存在不同的人SCC， SCC亚型。在目标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。在目标2中，Kohanski博士将检验SCC介导的上皮细胞 信号通过双孔钾通道发生。在目标2a中，他将利用尤辛室， 确定炎症或SCC丰度是否影响K2 P通道功能。在目标2b中，他将使用 具有双孔钾通道或SCC味道缺陷的小鼠品系的尘螨炎症模型 转导以确定炎症是否放大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指导和课程将提供博士。 Kohanski与基金会合作，成为一名专注于上皮化学感受的独立研究者。 细胞功能以及对粘膜免疫应答和炎性气道疾病的影响。

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.