人类代谢型老年聋的小鼠模型以及相关人体颞骨的研究

老年性耳聋是人类最主要的听力损失原因，它影响了近一半的65岁以上老年人。内耳的非感觉细胞，特别是耳蜗侧壁的纤维细胞与年龄相关的听觉功能下降密切相关。前期研究表明凋亡是耳蜗细胞随着年龄缺失的一个主要机理，同时人类颞骨的相关研究证明了代谢型老年聋是老年聋的主要病理原因。基于以上研究基础，本项目拟应用庚醇经圆窗膜给药，建立啮齿类动物体内代谢型老年聋的模型，使用免疫组织化学方法与电镜技术，研究耳蜗侧壁血管纹、螺旋韧带非感觉细胞的凋亡及分化；并分析耳蜗侧壁变性和更新的基因调控水平；再将这些结果应用于人类颞骨的研究，有望得出代谢型老年聋的病理生理机制，了解老年聋非感觉细胞变性与更新的分子机制；最终论证，螺旋韧带的纤维细胞凋亡以及减低的更新能力是耳蜗侧壁变性和老年性耳聋的主要原因这一假说。这将革新年龄相关耳蜗非感觉细胞的凋亡及再生理论，为未来人体干细胞移植的研究提供重要的实验基础。

Age-related hearing loss (presbyacusis) is the most common etiology of hearing loss in humans, affecting more than half of adults older than age 65. Evidence has shown that non-sensory cells in the inner ear, especially lateral wall fibrocytes, are integrally involved in age-related declines in auditory function. Cumulative evidence suggests that apoptosis is a major mechanism of cochlear cell loss in both aging and acute injury hearing loss. And cumulative evidence suggests that metabolic presbycusis is the dominant pathology in human temporal bone. Based on this evidence, we hypothesize that apoptosis and reduced replicating capacity in spiral ligament fibrocytes are responsible for cochlear lateral wall degeneration and subsequent hearing loss in the aging inner ear. We will apply heptanol to the round window niche of CBA/CaJ mice. To further characterize lateral wall degeneration, we will focus on apoptosis and proliferation of non-sensory cells in the stria vascularis and spiral ligament using immunohistochemistry and electron microscopy. Then utilize gene microarray and protein analysis to define gene expression profiles of fibrocyte apoptosis and turnover. Results are used to study in human cochlear tissues obtained from temporal bones from younger and older adult donors. Our proposed study promises to generate definitive data on the molecular mechanisms of cochlear non-sensory cell degeneration and replenishment. Insight into the molecular pathways of fibrocyte degeneration and replenishment has the potential to revolutionize investigations of the aging cochlea and non-sensory cell turnover. A better understanding of these processes is a critical step before future endeavors involving stem cells and translational studies with human subjects can be undertaken.