Cytokines on Olfactory Receptor Neuron Function

描述（由申请人提供）：本提案的目标是提供一个良好的监督，结构化的培训计划，将促进申请人的技术和智力技能的发展，作为一个独立的医生，科学家的成功。这将通过约翰霍普金斯耳鼻喉科、导师的分子生物学和遗传学基础科学系以及过敏和哮喘中心的协调努力来实现。该项目将允许候选人通过一个集中的，指导性的计划来研究炎症介质对嗅觉受体神经元（ORN）功能的影响，以追求他对慢性鼻窦炎嗅觉丧失机制的兴趣。 研究项目：嗅觉丧失是慢性鼻窦炎（CRS）的常见症状，显著降低受影响患者的生活质量。CRS中嗅觉功能障碍的细胞和分子机制仍不清楚。PI最近的研究表明，一些细胞因子调节孤立的ORN中的钙稳态。该建议的中心假设是慢性鼻窦炎中存在的炎症介质直接调节ORN功能，并通过气味反应的脱敏促进嗅觉丧失。 因此，本建议旨在了解细胞因子对ORN功能的影响，在体外和体内。具体而言，申请人将1）鉴定ORN上对CRS中重要介质特异的细胞因子受体，并证明这些介质对ORN气味诱导的反应的直接作用; 2）开发转基因小鼠模型，其中细胞因子可以在嗅上皮中诱导表达;和3）确定长期暴露于细胞因子对嗅觉受体神经元功能的影响，并广泛评估蛋白激酶，转录因子，和环核苷酸。 培训计划：申请人将参加一个教学计划，以提高他的职业发展。他将旁听约翰霍普金斯大学有关伦理学、研究设计和信号转导机制的课程。他还将参与神经科学，耳鼻喉科和免疫学的智力活动。将经常安排与赞助者举行会议，以监测进展情况。兰德尔·里德博士将提供主要赞助，大部分工作将在他的实验室进行。额外的实验室研究将在Schleimer博士的实验室进行，Schleimer博士是一位在气道炎症和细胞因子调节细胞功能方面具有专业知识的知名科学家。

DESCRIPTION (provided by applicant): The goal of this proposal is to provide a well-supervised, structured training program that will promote the development of the applicant's technical and intellectual skills necessary for success as an independent physician-scientist. This will be accomplished by a coordinated effort in the Johns Hopkins Department of Otolaryngology, the mentors' Basic Science Department of Molecular Biology and Genetics, and the Allergy and Asthma Center. The project will allow the candidate to pursue his interest in the mechanisms of olfactory loss in chronic sinusitis through a focused, mentored plan to study the effects of inflammatory mediators on olfactory receptor neuron (ORN) function. Research Program: Olfactory loss is a common symptom of chronic rhinosinusitis (CRS) that markedly diminishes quality of life of affected patients. The cellular and molecular mechanisms underlying olfactory dysfunction in CRS remain unknown. Recent studies by the PI show that some cytokines modulate calcium homeostasis in isolated ORNs. The central hypothesis of this proposal is that inflammatory mediators present in chronic rhinosinusitis directly modulate ORN function and promote the loss of olfaction through desensitization of the odor response. Accordingly, this proposal seeks to understand the effects of cytokines on ORN function in vitro and in vivo. Specifically, the applicant will 1) identify cytokine receptors on ORNs specific for mediators important in CRS and demonstrate the direct effects of these mediators on ORN odorant-induced responses; 2) develop a transgenic mouse model in which cytokines can be inducibly expressed in the olfactory epithelium; and 3) determine the effect of chronic exposure to cytokines on olfactory receptor neuron function and broadly assess the contribution of protein kinases, transcription factors, and cyclic nucleotides in this process. Training Program: The applicant will participate in a didactic program to enhance his career development. He will audit courses at Johns Hopkins University relating to ethics, research design, and the mechanisms of signal transduction. He will also participate in intellectual activities in Neuroscience, Otolaryngology, and Immunology. Frequent meetings with the sponsors will be arranged to monitor progress. Dr. Randall Reed, in whose laboratory the majority of the work will be performed, will provide primary sponsorship. Additional bench research will be performed in the laboratory of Dr. Schleimer, an established scientist with expertise in airway inflammation and cytokine modulation of cell function.