Mechanisms of Biological Aging of Cochlear Hair Cells

听力损失是人类最常见的听力损失形式，通常由以下原因引起： 耳蜗内毛细胞和外毛细胞（IHC、OHC）的退行性变化（或生物老化）和凋亡。 尽管已经使用各种小鼠模型对ARHL进行了广泛的研究，但毛细胞损伤的原因仍然是多方面的。 衰老和细胞凋亡在很大程度上仍是未知的。我们的长期目标是检查细胞和分子 IHC和OHC的生物老化机制。在建议的第一部分，我们将试图回答 耳蜗毛细胞如何经历衰老，以及为什么毛细胞退化的两个关键问题， 从基底转向顶转向外毛细胞转向内毛细胞。在第二部分中，我们将专注于分子 为什么OHC比IHC更容易受到老化或其他损伤的机制，通过确定 Clu，一种在OHC中差异表达的基因。一系列的电生理，免疫组织化学， 先进的成像和分子生物学技术将用于检查细胞超微结构的变化 以及耳蜗底部和顶端的IHC和OHC的机械和电生理特性， CBA/J系小鼠衰老过程中的变化。我们的毛细胞特异性RNA-seq实验使用IHC和 从年轻和衰老小鼠中获得的OHC将使我们能够通过识别基因来揭示分子机制 IHC和OHC的潜在年龄相关变化。我们有三个具体目标。目标1是检查 老化过程中毛细胞的机械传导和机械及电生理特性的变化。 目的2是研究内毛细胞衰老的分子机制下基因表达的变化， OHC。目的3是检验OHC中Clu表达水平相对于IHC的升高发挥作用的假设。 在OHC对衰老的选择性易感性中起关键作用。完成这些目标对于理解 毛细胞老化的内在细胞和分子机制。从这项研究中获得的知识也是 这对于确定旨在减缓ARHL的治疗干预目标至关重要。

Age-related hearing loss (ARHL), the most prevalent form of hearing loss in humans, is commonly caused by degenerative changes (or biological aging) and apoptosis of the cochlear inner and outer hair cells (IHCs, OHCs). Despite the fact that ARHL has been extensively studied using various mouse models, the causes of hair cell aging and apoptosis are still largely unknown. Our long-term goal is to examine the cellular and molecular mechanisms of biological aging of IHCs and OHCs. In the first part of the proposal we will attempt to answer two critical questions of how cochlear hair cells undergo aging, and why hair cell degeneration proceeds from the basal to the apical turn and from OHCs to IHCs. In the second part, we will focus on the molecular mechanisms of why OHCs are more susceptible to aging or other insults than IHCs by determining the roles of Clu, a gene that is differentially expressed in OHCs. A battery of electrophysiological, immunohistochemical, advanced imaging, and molecular biological techniques will be used to examine cellular changes in ultrastructure and mechanical and electrophysiological properties of IHCs and OHCs in the base and apex of the cochlea, respectively, in CBA/J strain mice during aging. Our hair cell-specific RNA-seq experiments using IHCs and OHCs obtained from younger and aging mice will enable us to reveal molecular mechanisms by identifying genes underlying age-related changes in IHCs and OHCs. We have three specific aims. Aim 1 is to examine the changes in mechanotransduction and mechanical and electrophysiological properties of hair cells during aging. Aim 2 is to examine the changes in gene expression underlying molecular mechanisms of aging of IHCs and OHCs. Aim 3 is to test the hypothesis that the elevated levels of Clu expression in OHCs relative to IHCs play a key role in the OHC’s selective susceptibility to aging. Completion of these aims is critical to understand the intrinsic cellular and molecular mechanisms of hair cell aging. The knowledge gained from this research is also essential for identifying targets for therapeutic intervention that aims to decelerate ARHL.