Enhancement of olfactory neuron survival and targeting via odorant exposure

描述(申请人提供)：作为一名具有丰富的嗅觉研究背景和嗅觉障碍临床评估经验的耳鼻喉科医生，我拥有将这两个学科结合起来寻找医疗疗法的独特机会。这项研究生涯发展计划包括五年的辅导培训，通过设计和实施拟议的项目。新技术、统计学、动物和人类研究的伦理以及负责任的研究工作方面的课程将补充这一培训。詹姆斯·施沃布博士在塔夫茨大学医学院的实验室将提供支持、设备、课程和整体教育环境，以完成该提案的研究和培训目标。我的长期职业目标是成为马萨诸塞州眼耳医院嗅觉领域的独立调查员，以便为患有嗅觉障碍的患者开发有效的治疗方法。 这项研究计划将探讨这样一种假设，即在损伤恢复过程中，定向气味暴露竞争性地增强受体特异性嗅觉神经元的存活和轴突靶向性，并且这种影响发生在嗅球和嗅觉上皮水平。这一假设将通过三个特定的目标进行验证，所有这些目标都利用小鼠从甲基溴暴露或嗅神经横断中恢复的模型。具体目标1将寻找鼻孔关闭后上皮内几种不同嗅觉受体亚型数量的正常化，并将评估消除气味诱导的活动对轴突靶向的影响。然后，特定目标2将表明，选择性重复气味暴露在嗅觉感受性神经元的存活和轴突靶向方面提供了竞争优势。然后，特定目标3将证明，在特定目标2中观察到的增强存活率可以在没有目标器官的情况下发生，并支持CREB在这一过程中的作用。 综上所述，这一建议确定了反复接触气味对损伤后嗅觉恢复的影响。它提供了更多关于系统如何试图自我治愈的机制的研究领域，最重要的是，从这项工作中获得的信息与旨在逆转人类嗅觉障碍的疗法的开发有关。

DESCRIPTION (provided by applicant): As an Otolaryngologist with a rich background in olfactory research and experience with the clinical assessment of olfactory disorders, I am positioned with the unique opportunity to combine these two disciplines in the search for medical therapies. This research career development plan consists of five years of mentored training through the design and implementation of the proposed project. Courses in new techniques, statistics, the ethics of animal and human studies, and the responsible conduct of research will supplement this training. The lab of Dr. James Schwob within Tufts University School of Medicine will provide the support, equipment, coursework, and overall educational environment to complete the research and training objectives of this proposal. My long-term career goal is to become an independent investigator within the area of olfaction at the Massachusetts Eye and Ear Infirmary in order to develop effective therapies for patients suffering from olfactory disorders. This research proposal will investigate the hypothesis that directed odorant exposure competitively enhances the survival and axonal targeting of receptor-specific olfactory neurons during recovery from lesion and that this effect occurs at the level of both the olfactory bulbs and olfactory epithelium. The hypothesis will be tested through three specific aims all utilizing the mouse model of recovery from methyl bromide exposure or olfactory nerve transection. Specific Aim 1 will look for the normalization in numbers of several different olfactory receptor subtypes within the epithelium after nares closure and will assess the effect of removing odor-induced activity on axon targeting. Specific Aim 2 will then show that selective repeated odorant exposure provides a competitive advantage in survival and axon targeting for the receptive olfactory neurons. Specific Aim 3 will then demonstrate that the enhanced survival observed in Specific Aim 2 can occur without the target organ and supports the role of CREB in this process. In summary, this proposal determines the effect of repeated odorant exposure on the recovery of the sense of smell after injury. It provides additional areas of research on the mechanisms of how the system attempts to heal itself, and most importantly, the information gained from this work is relevant for the development of therapies aimed at reversing sense of smell disorders in humans.