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监督良好的、有组织的培训计划，以促进申请人作为一名独立的内科科学家取得成功所必需的技术和智力技能的发展。这将通过约翰霍普金斯大学耳鼻喉科、分子生物学和遗传学导师基础科学部以及过敏和哮喘中心的协调努力来实现。该项目将允许应试者通过一个有重点的、有指导的计划来研究炎症介质对嗅觉感受器(ORN)功能的影响，从而对慢性鼻窦炎的嗅觉丧失机制感兴趣。 研究计划：嗅觉丧失是慢性鼻-鼻窦炎(CRS)的常见症状，显著降低受影响患者的生活质量。CRS嗅觉功能障碍的细胞和分子机制尚不清楚。PI最近的研究表明，一些细胞因子调节离体卵母细胞的钙稳态。这一建议的中心假设是，慢性鼻-鼻窦炎中存在的炎症介质直接调节ORN功能，并通过脱敏气味反应促进嗅觉丧失。 因此，这项建议试图了解细胞因子在体外和体内对ORN功能的影响。具体地说，申请人将1)确定在CRS中重要的介质在ORN上的细胞因子受体，并展示这些介质对ORN气味诱导的反应的直接影响；2)建立细胞因子可在嗅觉上皮细胞中诱导表达的转基因小鼠模型；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在这一过程中的作用。 培训计划：申请者将参加一项旨在促进其职业发展的教学计划。他将审核约翰·霍普金斯大学与伦理学、研究设计和信号转导机制有关的课程。他还将参与神经科学、耳鼻喉科和免疫学的智力活动。将安排与赞助者的频繁会议，以监测进展情况。兰德尔·里德博士将提供主要赞助，他的实验室将完成大部分工作。其他的试验台研究将在施莱默博士的实验室进行，施莱默博士是一位在呼吸道炎症和细胞功能的细胞因子调节方面拥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.