The role of Pou4f3 in age-related vestibular dysfunction

项目总结： 据估计，超过40%的老年人患有前庭(即平衡)缺陷。 这些损失会导致许多其他与衰老相关的问题，包括认知能力下降。 以及伤害性或致命的坠落。与年龄相关的前庭功能障碍之间也有很强的联系 (ARVD)和阿尔茨海默病及相关痴呆。尽管这些问题普遍存在 以及它们对公共健康造成的巨大损失和相关的财务成本，潜在的 ARVD的病因目前知之甚少。因此，目前没有FDA批准的 ARVD的治疗方法。虽然对机械性原因缺乏深入的理解，但它已经 一段时间以来，人们就知道一种导致年龄相关内耳的非常常见的病理 功能障碍是被称为毛细胞的感觉细胞的死亡。为什么这些细胞会随着年龄的增长而死亡 仍然是个谜。在这里，我们已经确定了一种以前未描述的模式 促进生存基因Pou4f3的表达，该基因通常在内耳高表达 毛细胞，但随着年龄的增长而下调，其方式与毛细胞死亡有关 平衡内耳的器官。此外，初步数据表明，删除Pou4f3 导致前庭毛细胞的有害表型，加剧毛细胞死亡，并导致 前庭功能显著下降。我们建议以这些初步数据为基础，通过 进一步检测Pou4f3在前庭器官中的表达随年龄的变化以及在模型中的变化 阿尔茨海默氏症。我们还将更彻底地描述Pou4f3缺失的影响 更好地理解缺失或性欲减退对平衡和神经学的影响 功能。我们还建议检测内耳组织中的基因组调控元件。 年轻和老年小鼠也确定Pou4f3随年龄下调的原因机制 因为可能会发现内耳中与衰老过程有关的其他关键基因。最后，我们 将测试Pou4f3的过度表达是否可以防止感觉细胞死亡和年龄相关 前庭下降。我们的初步数据表明Pou4f3是一个很有前途的治疗靶点 在老龄化的人类人口中保持平衡功能。拟议中的实验将 确定这一总体假设的有效性，并将提供一个基础，以 启动Pou4f3靶向药理和基因治疗的几项新研究 预防老年性前庭萎缩的方法。

Project Summary: It has been estimated that more than 40% of older adults suffer vestibular (i.e. balance) deficits. These losses cause numerous other problems associated with aging including cognitive decline and injurious or fatal falls. There is also a strong link between age-related vestibular dysfunction (ARVD) and Alzheimer's disease and related dementias. Despite the prevalence of these issues and the massive toll they exert on public health and associated financial costs, the underlying causes for ARVD are poorly understood. As a result, there are currently no FDA approved therapies for ARVD. While a deep understanding of mechanistic causes is lacking, it has been known for some time that a very common pathology that causes age related inner ear dysfunction is the death of sensory cells called hair cells. Exactly why these cells die with age remains a mystery. Here, we have identified a previously uncharacterized pattern in the expression of the pro-survival gene, Pou4f3, where it is normally highly expressed in inner ear hair cells, but is downregulated with age in a fashion that is correlated with hair cell death in the balance organs of the inner ear. Furthermore, preliminary data suggest that deleting Pou4f3 causes detrimental phenotypes in vestibular hair cells, exacerbates hair cell death, and leads to significant declines in vestibular function. We propose to build on these preliminary data by further examining Pou4f3 changes in expression in vestibular organs with age and in models of Alzheimer's disease. We will also more thoroughly characterize the effects of Pou4f3 deletion to better understand the effects that deletion or hypomorhpism have on balance and neurological functions. We also propose to examine genomic regulatory elements in inner ear tissues from young and aged mice to identify causal mechanisms for Pou4f3 downregulation with age as well as possibly discover other key genes involved in aging processes in the inner ear. Finally, we will test whether overexpression of Pou4f3 can prevent sensory cell death and age related vestibular declines. Our preliminary data suggest that Pou4f3 is a promising therapeutic target for preserving balance function in the aging human population. The experiments proposed will determine the validity of that overarching hypothesis and will provide a foundation from which to launch several new investigations into Pou4f3-targeted pharmacological and gene therapy approaches for the prevention of age related vestibular decline.