MECHANISMS OF SENSORY REGENERATION

描述(申请人提供)：听力损失和眩晕是目前影响数百万美国人的严重健康问题。内耳的正常感觉功能依赖于机械感受性毛细胞，毛细胞将声音振动和头部运动转化为电信号，然后传送到大脑。由于噪音暴露、耳毒性药物、内耳感染或正常衰老的一部分，毛细胞可能会受到损伤或丢失。哺乳动物(包括人类)的内耳无法替代这些细胞，而毛细胞的死亡是感觉神经性耳聋最常见的原因。相比之下，非哺乳动物脊椎动物的耳朵在受伤后可以迅速再生毛细胞，了解这种再生过程的细胞学基础是非常有意义的。这项建议侧重于再生生物学的一个新的、相对未被探索的方面。先前的研究表明，巨噬细胞--先天免疫系统的主要效应细胞--在许多类型的体细胞组织的修复和再生中起着至关重要的作用。耳蜗和前庭器官含有大量巨噬细胞，但这些细胞在耳朵内的功能完全未知。我们之前的工作表明，巨噬细胞可能有助于促进毛细胞再生，但直接的证据仍然难以捉摸。拟议的研究将解决这些长期存在的问题，并将利用新开发的方法，在体外和体内选择性地消除成熟耳朵中的毛细胞和/或巨噬细胞。拟议的实验结果将表明巨噬细胞在再生过程中是起刺激作用还是抑制作用。值得注意的是，从这项工作中获得的知识也将扩展到再生医学领域之外。许多内耳病变对免疫抑制疗法有反应。这种治疗的细胞基础尚不清楚，但这些观察表明炎症细胞对耳朵感觉结构的直接影响。因此，这些项目的完成将解决许多关于耳廓巨噬细胞对感觉修复的贡献的悬而未决的问题，并将为天然免疫系统和内耳之间的细胞对话的性质提供新的见解。

DESCRIPTION (provided by applicant): Hearing loss and vertigo are serious health problems that currently affect millions of Americans. Normal sensory function of the inner ear relies on mechanoreceptive hair cells, which convert sound vibrations and head movements into electrical signals that are conveyed to the brain. Hair cells can be injured or lost as a result of noise exposure, ototoxic medications, inner ear infections, or as part of normal aging. The inner ears of mammals (including humans) are unable to replace these cells, and the death of hair cells is the most common cause of sensorineural deafness. In contrast, the ears of nonmammalian vertebrates can quickly regenerate hair cells after injury, and it is of great interest to understand the cellular basis of this regenerative process. This proposal focuses on a novel and relatively unexplored aspect of regenerative biology. Prior research has shown that macrophages - the primary effector cells of the innate immune system - are critically involved in repair and regeneration of many types of somatic tissues. The cochlea and vestibular organs contain large numbers of macrophages, but the function of those cells within the ear is completely unknown. Our prior work has suggested that macrophages may help promote hair cell regeneration, but a direct demonstration has remained elusive. The proposed studies will address these long-standing issues, and will make use of newly-developed methods for selective elimination of hair cells and/or macrophages from the mature ear, both in vitro and in vivo. The outcome of the proposed experiments will indicate whether macrophages play a stimulatory or suppressive role in regeneration. Notably, knowledge acquired from this work will also extend beyond the realm of regenerative medicine. Many inner ear pathologies respond to immunosuppressive therapies. The cellular basis of such treatments is unknown, but these observations point to direct effects of inflammatory cells on the sensory structures of the ear. As such, completion of these projects will resolve many outstanding questions regarding the contribution of otic macrophages to sensory repair and will also provide new insights into the nature of the cellular dialogue between the innate immune system and the inner ear.