The role of Pou4f3 in age-related vestibular dysfunction

项目摘要： 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与衰老相关的其他问题，包括认知能力下降 以及受伤或致命的福尔斯坠落。与年龄相关的前庭功能障碍 （ARVD）和阿尔茨海默病及相关痴呆。尽管这些问题普遍存在， 以及它们对公共卫生和相关财务成本造成的巨大损失， 对ARVD的病因知之甚少。因此，目前没有FDA批准 ARVD治疗。虽然缺乏对机械原因的深刻理解，但它一直是 一段时间以来，人们都知道一种非常常见的病理学， 功能障碍是一种叫做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，我们已经确定了一个以前没有特征的模式， 促存活基因Pou4f3的表达，其通常在内耳中高度表达 毛细胞，但随着年龄的增长下调的方式是与毛细胞死亡， 内耳的平衡器官。此外，初步数据表明，删除Pou4f3 导致前庭毛细胞中有害的表型，加剧毛细胞死亡，并导致 前庭功能显著下降。我们建议在这些初步数据的基础上， 进一步研究Pou4f3在前庭器官中表达随年龄的变化以及在 老年痴呆症我们还将更彻底地描述Pou4f3缺失对 更好地理解缺失或低智力对平衡和神经系统的影响 功能协调发展的我们还建议检查内耳组织中的基因组调控元件， 年轻和老年小鼠，以确定Pou4f3随年龄下调的因果机制 因为可能会发现其他与内耳衰老过程有关的关键基因。最后我们 将测试Pou4f3的过表达是否可以防止感觉细胞死亡和年龄相关的 前庭功能减退我们的初步数据表明，Pou4f3是一个有前途的治疗靶点 在老龄人口中保持平衡功能。提出的实验将 确定这一总体假设的有效性，并将提供一个基础， 启动了几项针对Pou4f3的药理学和基因治疗的新研究 预防与年龄相关的前庭衰退的方法。

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.