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
基本信息
- 批准号:10619025
- 负责人:
- 金额:$ 64.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:129 Mouse3xTg-AD mouseATAC-seqAdultAgeAge MonthsAgingAllelesAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAnimalsAuditoryC57BL/6 MouseCell DeathCell SurvivalCellsCessation of lifeClassificationCochleaDNADataDevelopmental GeneDown-RegulationEarElderlyEmbryonic DevelopmentEpitheliumEquilibriumExhibitsFDA approvedFemaleFinancial costFoundationsFunctional disorderGenesGeneticGenomicsHair CellsHealthHealthcareHearingHumanImpaired cognitionInjectionsInner Hair CellsInvestigationLabyrinthLinkLocationModelingMotorMusMutationNervous System PhysiologyOrganPathologyPatternPhenotypePopulationPresbycusisPrevalencePrevention approachProcessPublic HealthQuality of lifeReflex actionRegulationRegulatory ElementRoleSensorimotor functionsSensorySensory HairSex DifferencesSynapsesSystemTamoxifenTask PerformancesTemporal bone structureTestingTimeTissuesVestibular Function TestsVestibular Hair Cellsage relatedagedcell agecognitive functioncognitive performancecostexperimental studyfallsgene therapygenetic deafnessimmunoreactivitymalemorris water mazemouse modelnoise exposurenovelobject recognitionoverexpressionpharmacologicpostnatalpreservationpreventprogressive hearing lossresponsetherapeutic targettranscription factor
项目摘要
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.
项目概要:
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
以及受伤或致命的跌倒。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症。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,
ARVD 的病因尚不清楚。因此,目前尚无 FDA 批准的
ARVD 的治疗方法。虽然缺乏对机械原因的深入了解,但已经
一段时间以来,我们知道一种非常常见的病理现象会导致与年龄相关的内耳
功能障碍是指称为毛细胞的感觉细胞的死亡。这些细胞随着年龄的增长而死亡的确切原因
仍然是一个谜。在这里,我们发现了一个以前未表征的模式
促生存基因 Pou4f3 的表达,该基因通常在内耳中高度表达
毛细胞,但随着年龄的增长而下调,其方式与毛细胞死亡相关
内耳的平衡器官。此外,初步数据表明删除 Pou4f3
导致前庭毛细胞有害的表型,加剧毛细胞死亡,并导致
前庭功能显着下降。我们建议以这些初步数据为基础
进一步检查 Pou4f3 在前庭器官中随年龄和模型的表达变化
阿尔茨海默病。我们还将更全面地描述 Pou4f3 删除对
更好地理解缺失或低形态对平衡和神经系统的影响
功能。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
并可能发现参与内耳衰老过程的其他关键基因。最后,我们
将测试 Pou4f3 的过度表达是否可以预防与年龄相关的感觉细胞死亡
前庭功能下降。我们的初步数据表明 Pou4f3 是一个有前途的治疗靶点
维持老龄化人口的平衡功能。所提出的实验将
确定该总体假设的有效性,并将提供一个基础
对 Pou4f3 靶向药理学和基因治疗开展多项新研究
预防与年龄相关的前庭衰退的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brandon C. Cox其他文献
Transport of multiple nicotinic acetylcholine receptors in the rat optic nerve: high densities of receptors containing α6 and β3 subunits
大鼠视神经中多种烟碱乙酰胆碱受体的转运:含有α6和β3亚基的高密度受体
- DOI:
10.1111/j.1471-4159.2008.05282.x - 发表时间:
2008-06-01 - 期刊:
- 影响因子:4.7
- 作者:
Brandon C. Cox;Andrea M. Marritt;D. Perry;K. Kellar - 通讯作者:
K. Kellar
Brandon C. Cox的其他文献
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{{ truncateString('Brandon C. Cox', 18)}}的其他基金
Consequences of chronic noise exposure in nonhuman primates
非人类灵长类动物长期暴露于噪音的后果
- 批准号:
10608454 - 财政年份:2022
- 资助金额:
$ 64.04万 - 项目类别:
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:
10468947 - 财政年份:2021
- 资助金额:
$ 64.04万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 64.04万 - 项目类别:
p16INK4a in Cochlear Hair Cell Regeneration.
p16INK4a 在耳蜗毛细胞再生中的作用。
- 批准号:
8076759 - 财政年份:2009
- 资助金额:
$ 64.04万 - 项目类别:
p16INK4a in Cochlear Hair Cell Regeneration.
p16INK4a 在耳蜗毛细胞再生中的作用。
- 批准号:
8064638 - 财政年份:2009
- 资助金额:
$ 64.04万 - 项目类别:
p16INK4a in Cochlear Hair Cell Regeneration.
p16INK4a 在耳蜗毛细胞再生中的作用。
- 批准号:
7753757 - 财政年份:2009
- 资助金额:
$ 64.04万 - 项目类别:
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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
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