COCHLEAR HOMEOSTASIS

本研究的目的是探讨耳蜗炎症细胞因子诱导听力损失的机制。我们的研究重点是螺旋韧带，因为我们最近的研究表明，螺旋韧带1)在耳蜗液和离子稳态中起着关键作用，2)可能特别容易受到炎症过程的影响。1型纤维细胞是螺旋韧带内最常见的细胞类型。它们是耳蜗支持细胞合胞体的一部分，由称为间隙连接的细胞间连接连接。我们假设这个缝隙连接这个缝隙连接系统对于钾离子从Corti器官到血管纹并最终进入内淋巴的再循环至关重要，在内淋巴中，高钾水平对正常的高细胞功能至关重要。我们还发现，1型纤维细胞含有高水平的转录因子NFkappaB，这种蛋白质在组织对创伤或感染的急性期炎症反应中起关键作用。在其他组织中，NFkappaB诱导的炎症细胞因子可破坏间隙功能传导。我们的工作假设是，耳蜗的炎症过程，由多种疾病状态引起，诱导螺旋韧带中的细胞因子，从而阻断1型纤维细胞之间的间隙连接，剥夺血管纹的钾供应，产生严重的感音神经性听力损失。我们将通过描述给药或诱导细胞因子后耳蜗的生理和细胞化学反应来检验这一假设。我们将通过测量诱发电位和内淋巴电位来测量耳蜗功能的变化，并将利用免疫细胞化学来记录在药理学实验后耳蜗细胞细胞化学成分的变化，以确定细胞因子作用的机制。这些结果可能会对各种常见但知之甚少的耳科疾病（如迷路炎、耳硬化、涉及间隙连接蛋白的遗传性听力损失和免疫介导的听力损失）的感音神经性听力损失的基础提供相当大的帮助。耳蜗内炎症过程的细胞化学底物的表征可能有助于设计治疗或预防与这些疾病相关的听力损失的方法。

The goal of the proposed work is to explore mechanisms of hearing loss induced by inflammatory cytokines in the cochlea. The work focused on the spiral ligament, because our recent work suggests that it 1) plays a critical role in cochlear fluid and ion homeostasis and 2) may be particularly susceptible to inflammatory processes. Type 1 fibrocytes are the most common cell type within the spiral ligament. They are part of a syncytium of cochlear supporting cells joined by intercellular connections called gap junctions. We have hypothesized that this gap junctional that this gap junctional system is essential for potassium ion recirculation from the organ of Corti to the stria vascularis and ultimately into endolymph, where a high potassium level is critical for normal high cell function. We have also found that type 1 fibrocytes contain high levels of the transcription factor NFkappaB, a protein that plays a key role in the acute phase inflammatory response of tissue to trauma or infections. In other tissues, inflammatory cytokines induced by NFkappaB can disrupt gap functional conductivity. Our working hypotheses is that inflammatory processes in the cochlea, arising from a wide array of disease states, induce cytokines in the spiral ligament, thereby blocking gap junctions between type 1 fibrocytes, depriving the stria vascularis of its potassium supply and producing profound sensorineural hearing loss. We will test this hypothesis by characterizing physiological and cytochemical responses of the cochlea following administration or induction of cytokines. We will measure changes in cochlear function by measuring evoke potentials and the endolymphatic potential and will use immunocytochemistry to document changes in cytochemical constituents of cochlear cells following the pharmacological experiments in order to determine the mechanisms underlying the cytokines' effects. The results may shed considerable light on the bases for sensorineural hearing loss in a variety of common, but poorly understood, otological disorders such as labyrinthitis, otosclerosis, genetic hearing losses involving gap junction proteins, and immune-mediated hearing loss. The proposed characterization of cytochemical substrates of inflammatory processes within the cochlea may help devise treatments or means of preventing hearing loss associated with these disorders.