Macrophage Response to Otic Pathology

听觉和平衡感是由内耳的耳蜗器和前庭器官调节的。在……里面 这些器官的机械运动(由声音振动或头部运动产生)是由 感觉毛细胞，并通过听觉和前庭神经传递到大脑。毛细胞是人体所必需的 感觉功能，但可因噪音暴露、耳毒性或感染而受损，也可作为 正常衰老的后果。损伤后，细胞碎片从感觉上皮及时清除 有助于促进修复和动态平衡。这一过程由两种不同的细胞类型介导：(1)支持细胞， 它可以吞噬细胞碎片，并--在非哺乳动物脊椎动物中--产生替代毛细胞，以及(2) 巨噬细胞，这是先天免疫系统的效应细胞，也识别和吞噬死亡的细胞。 支持细胞存在于所有含有毛细胞的上皮细胞中。内耳的组织也含有 巨噬细胞驻留群体和巨噬细胞介导的炎症发生在大多数类型的耳聋后 受伤。在应对毛细胞损伤时，正确的支持细胞和巨噬细胞都是至关重要的 区分健康细胞和濒临死亡的细胞，然后只瞄准并移除那些不可逆转的细胞 损坏了。这个项目的一个关键目标是了解这一过程是如何发生的。一组实验将会 研究已知在巨噬细胞和巨噬细胞中激发吞噬反应所必需的信号通路 其他类型的细胞，但以前从未在内耳中进行过研究。此外，我们将确定是否 急性损伤后抑制吞噬功能可能会允许一些受损的毛细胞存活，以及 吞噬受损的毛细胞是感官再生的重要触发因素。研究将同时使用这两种方法 哺乳动物和斑马鱼模型，以最大限度地利用这两个系统的独特优势。第二盘 实验将增强我们对炎症在前庭器官中的作用的非常有限的了解。 项目将专注于两种临床相关的情况。首先，众所周知，产前感染与 巨细胞病毒(CMV)可导致听力和平衡发育障碍，但潜在的 机制是完全未知的。使用经过验证的小鼠模型，我们已经证明了CMV感染 导致前庭黄斑的大量炎症反应，伴随着吞噬 感觉细胞。我们将确定这种炎症是否是巨细胞病毒诱导的病理的原因，以及 巨噬细胞是否将巨细胞病毒运送到前庭外周。更多的研究将描述 人工耳蜗植入小鼠模型的前庭损伤和炎症。研究工作完成后， 极大地增强了目前对调节内耳炎症的细胞信号的了解。是这样的 知识将允许开发调节这种炎症的方法，从而减少病理 促进损伤后的功能恢复。

The senses of hearing and balance are mediated by the cochlea and vestibular organs of the inner ear. In these organs, mechanical motion (generated either by sound vibrations or by head movements) is detected by sensory hair cells and transmitted to the brain by the auditory and vestibular nerves. Hair cells are essential for sensory function, but can be injured by noise exposure, ototoxicity or infections, and are also lost as a consequence of normal aging. After injury, the timely removal of cellular debris from the sensory epithelium helps promote repair and homeostasis. This process is mediated by two distinct cell types: (1) Supporting cells, which can engulf cellular debris and – in nonmammalian vertebrates – generate replacement hair cells, and (2) Macrophages, which are effector cells of the innate immune system that also recognize and engulf dying cells. Supporting cells are present in all hair cell-containing epithelia. The tissues of the inner ear also contain resident populations of macrophages, and macrophage-mediated inflammation occurs after most types of otic injury. When responding to hair cell injury, it is critical that both supporting cells and macrophages correctly distinguish between healthy and dying cells, and then target and remove only those cells that are irreversibly damaged. A key objective of this project is to understand how this process occurs. One set of experiments will examine a signaling pathway known to be essential for evoking phagocytic responses in macrophages and other cell types, but has not been previously studied in the inner ear. In addition, we will determine whether inhibiting phagocytosis after acute injury may permit some damaged hair cells to survive, and whether the engulfment of injured hair cells is an important trigger for sensory regeneration. Studies will employ both mammalian and zebrafish models, in order to best utilize the unique advantages of both systems. A second set of experiments will enhance our very limited knowledge of the role of inflammation in the vestibular organs. Projects will focus on two clinically relevant situations. First, it is known that prenatal infection with cytomegalovirus (CMV) can cause developmental deficits in both hearing and balance, but the underlying mechanisms are completely unknown. Using a validated mouse model, we have shown that CMV infection leads to a massive inflammatory response in the vestibular maculae, which is accompanied by phagocytosis of sensory cells. We will determine whether this inflammation is the cause of CMV-induced pathology and also whether macrophages transport CMV into the vestibular periphery. Additional studies will characterize vestibular injury and inflammation in a mouse model of cochlear implantation. Completion of the studies will greatly enhance current knowledge of the cellular signals that regulate inflammation in the inner ear. Such knowledge will permit development of methods for modulating such inflammation, so as to reduce pathology and enhance functional recovery after injury.