Enhancement of olfactory neuron survival and targeting via odorant exposure

作为一名耳鼻喉科医生，具有丰富的嗅觉研究背景和临床经验 嗅觉障碍的评估，我有独特的机会将这两者结合起来 在寻找医学疗法方面的学科。这项研究的职业发展计划包括五年 通过设计和实施拟议的项目，开展有指导的培训。新课程中的 技术、统计学、动物和人类研究的伦理以及负责任的研究行为将 补充此培训。塔夫茨大学医学院詹姆斯·施沃布博士的实验室将 为完成研究提供支持、设备、课程和整体教育环境 以及这项建议的培训目标。我的长期职业目标是成为一名独立调查员 在马萨诸塞州眼耳医院的嗅觉区域内，以开发有效的 嗅觉障碍患者的治疗。 这项研究提案将调查竞争性地定向气味暴露的假设 增强受体特异性嗅觉神经元在损伤恢复期间的存活和轴突靶向性 这种影响发生在嗅球和嗅觉上皮细胞的水平上。假说 将通过三个特定的目标进行测试，所有这些都利用从甲基溴中回收的小鼠模型 暴露或嗅神经切断。具体目标1将在几个数字中寻找归一化 不同的嗅觉感受器亚型在鼻孔关闭后的上皮内，并将评估 消除气味诱导的轴突靶向活动。然后，特定目标2将显示选择性重复 气味暴露为接受嗅觉的生存和轴突靶向提供了竞争优势 神经元。然后，具体目标3将证明，在没有SA2的情况下，观察到的增强的存活率可以发生 它是目标机构，并支持CREB在这一进程中的作用。 综上所述，这项建议决定了重复接触气味对恢复 受伤后的嗅觉。它提供了关于系统如何运行的机制的其他研究领域 试图自我治愈，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治疗方法的开发。

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 SA2 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.