MECHANISMS OF SENSORY REGENERATION

 描述（由申请人提供）：内耳的正常功能需要机械感受毛细胞的存在，其将声音振动和头部运动转化为传达到大脑的电信号。毛细胞可能会受伤或失去作为一个结果 噪声暴露、耳毒性药物、内耳感染或作为正常衰老的一部分。人耳不能替代毛细胞，毛细胞的丧失是感音神经性耳聋和平衡障碍的主要原因。然而，值得注意的是，非哺乳类脊椎动物的耳朵在受伤后可以迅速再生毛细胞。对这种再生过程的细胞基础的更完整的理解可能会建议在人耳中诱导类似形式的再生的方法。大多数关于毛细胞再生的正在进行的研究集中在感觉上皮内细胞的内在特性上。相比之下，拟议的研究将检查感觉上皮是如何由其支持（基质）组织和巨噬细胞调节的。我们之前的工作已经表明，巨噬细胞-先天免疫系统的主要效应细胞-积极清除垂死毛细胞的碎片，但将巨噬细胞招募到受伤耳朵中的化学信号是完全未知的。一系列研究将评估几种候选化学引诱物在巨噬细胞募集过程中的作用，并确定巨噬细胞是否在耳毒性后积极促进毛细胞死亡。从这些工作中获得的知识将有超越再生医学的应用。许多内耳病理被认为涉及炎症，确定耳朵如何调节先天免疫可能会导致对此类疾病更有效的治疗。第二个系列的研究将探讨基质组织细胞如何影响耳朵感觉上皮细胞的修复和再生。利用新获得的基因组数据和新的培养技术，我们将确定细胞信号如何从基质传递到上皮，然后确定参与这一过程的候选基因。进一步的研究将揭示基质组织的组成是否限制了哺乳动物耳的再生，以及来自基质的信号是否调节了常驻干细胞的数量。总之，这些研究的结果将产生必要的知识，用于开发在损伤或与年龄有关的病理后"重建"内耳感觉结构的方法。

 DESCRIPTION (provided by applicant): Proper function of the inner ear requires the presence of 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 human ear cannot replace hair cells, and their loss is a leading cause of sensorineural deafness and balance disorders. It is notable, however, that the ears of nonmammalian vertebrates can quickly regenerate hair cells after injury. A more complete understanding of the cellular basis of this regenerative process is likely to suggest methods for inducing similar forms of regeneration in the human ear. Most ongoing research on hair cell regeneration is focused on the intrinsic properties of the cells that reside within the sensory epithelium. In contrast, the proposed research will examine how the sensory epithelium is regulated by its supporting (stromal) tissues and by macrophages. Our prior work has shown that macrophages - the primary effector cells of the innate immune system - actively remove the debris of dying hair cells, but the chemical signals that recruit macrophages into the injured ear are completely unknown. A series of studies will evaluate the role of several candidate chemoattractants in the process of macrophage recruitment, and also determine whether macrophages actively contribute to hair cell death after ototoxicity. Knowledge acquired from such work will have applications beyond regenerative medicine. Many inner ear pathologies are thought to involve inflammation, and identifying how the ear regulates innate immunity may lead to more effective therapies for such conditions. A second series of studies will explore how the cells of the stromal tissues influence repair and regeneration within the ear's sensory epithelia. Using newly-acquired genomic data and novel culture techniques, we will determine how cellular signals are transmitted from stroma to epithelium and then identify candidate genes that participate in this process. Additional studies will reveal whether the composition of the stromal tissues limits regeneration in the mammalian ear and also whether signaling from the stroma regulates the population of resident stem cells. Together, the outcomes of these studies will generate knowledge essential for the development of methods for `rebuilding' the sensory structures of the inner ear after damage or age-related pathologies.