The role of Pou4f3 in age-related vestibular dysfunction

Pou4f3 在年龄相关前庭功能障碍中的作用

• 批准号: 10277134
• 负责人: Brandon C. Cox
• 金额: $ 66.66万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277134
• 关键词: 129 Mouse; 3xTg-AD mouse; ATAC-seq; Adult; Age; Age-Months; Aging; Alleles; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animals; Auditory; C57BL/6 Mouse; Cell Death; Cell Survival; Cells; Cessation of life; Cochlea; DNA; Data; Developmental Gene; Down-Regulation; Ear; Elderly; Embryonic Development; Epithelial; Equilibrium; Exhibits; FDA approved; Female; Financial cost; Foundations; Functional disorder; Genes; Genetic; Genomics; Hair Cells; Health; Healthcare; Hearing; Human; Impaired cognition; Injections; Inner Hair Cells; Investigation; Labyrinth; Link; Location; Modeling; Motor; Mus; Mutation; Nervous System Physiology; Noise; Organ; Pathology; Pattern; Pharmacology; Phenotype; Population; Presbycusis; Prevalence; Prevention approach; Process; Public Health; Quality of life; Reflex action; Regulation; Regulatory Element; Role; Sensorimotor functions; Sensory; Sensory Hair; Sex Differences; Synapses; System; Tamoxifen; Task Performances; Temporal bone structure; Testing; Time; Tissues; Vestibular Function Tests; Vestibular Hair Cells; age related; aged; cell age; cognitive function; cognitive performance; cost; experimental study; falls; gene therapy; genetic deafness; immunoreactivity; male; morris water maze; mouse model; novel; object recognition; overexpression; postnatal; preservation; prevent; progressive hearing loss; response; therapeutic target; transcription factor

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.

项目摘要： 据估计，超过40％的老年人患有前庭（即平衡）缺陷。 这些损失导致与衰老有关的许多其他问题，包括认知能力下降 和有害或致命的瀑布。与年龄相关的前庭功能障碍之间也有很强的联系 （ARVD）和阿尔茨海默氏病和相关痴呆症。尽管存在这些问题 以及他们对公共卫生和相关财务成本造成的巨大损失，基础 ARVD的原因知之甚少。结果，目前尚未获得FDA批准 ARVD的疗法。尽管缺乏对机械原因的深刻理解，但 一段时间以来都知道导致年龄相关的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。确切为什么这些细胞随着年龄的增长而死 仍然是一个谜。在这里，我们在 促生存基因POU4F3的表达，通常在内耳高度表达 毛细胞，但随着年龄与毛细胞死亡相关的方式下调 平衡内耳的器官。此外，初步数据表明删除POU4F3 在前庭毛细胞中引起有害的表型，加剧毛细胞死亡，并导致 前庭功能的显着下降。我们建议通过 进一步研究POU4F3随着年龄和年龄和模型的前庭器官表达的变化 阿尔茨海默氏病。我们还将更彻底地表征POU4F3删除的影响 更好地理解删除或缺陷的影响对平衡和神经功能的影响 功能。我们还建议检查内耳组织中的基因组调节元件 年轻小鼠和老年小鼠识别POU4F3下调的因果机制，随着年龄的增长 因为可能发现了内耳衰老过程涉及的其他关键基因。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与年龄有关 前庭下降。我们的初步数据表明POU4F3是一个有前途的治疗靶标 用于保留人口老龄化的平衡功能。提出的实验将 确定该总体假设的有效性，并将提供一个基础 对靶向POU4F3的药理学和基因疗法进行了几项新研究 预防与年龄相关的前庭下降的方法。