Vestibular hair cell turnover in normal adult mammals

正常成年哺乳动物的前庭毛细胞更新

• 批准号: 8829225
• 负责人: Jennifer S. Stone
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829225
• 关键词: Adult; Age; Aging; American; Auditory; Cell Count; Cell Death; Cell Lineage; Cell division; Cells; Cessation of life; Chiroptera; Collaborations; Data; Diphtheria Toxin; Epithelium; Equilibrium; Excision; Functional disorder; Funding; Future; Genetic Programming; Goals; Hair Cells; Head Movements; Health; Hearing; Hippocampus (Brain); Homeostasis; Human; Illinois; Immune; Infection; Injury; Inner Ear Infection; Knock-in Mouse; Knowledge; Laboratories; Mammals; Methods; Molecular Profiling; Morphology; Movement; Mus; Natural regeneration; Olfactory Epithelium; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Population; Population Dynamics; Positioning Attribute; Process; Production; Proliferation Marker; Quality of life; Reporter; Reporting; Research; Research Personnel; Research Project Grants; Rodent; Sensory; Sensory Hair; Signal Transduction; Supporting Cell; Symptoms; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Type I Hair Cell; Type II Hair Cell; Universities; Utricle structure; Utricular macula; Vertebrates; Vestibular Hair Cells; Work; age related; aged; base; cell type; equilibration disorder; fall risk; gaze; hair cell regeneration; improved; innovation; insight; medical schools; neurotransmission; novel therapeutic intervention; premature; progenitor; programs; relating to nervous system; response to injury; transdifferentiation; young adult

DESCRIPTION (provided by applicant): Many Americans suffer from vestibular dysfunction, which can reduce the quality of life and increase the risk for falls and premature death. A major cause of vestibular dysfunction is the loss of hair cells (HCs), which transduce head movements into neural signals and allow us to maintain gaze, orientation, and control of body movements. Vestibular HCs die as a result of ototoxic drug treatments, inner ear infection, and changes associated with aging. In mammals, vestibular HCs have historically been considered to be irreplaceable, since many symptoms associated with HC loss are permanent. However, several studies have shown that adult rodents can spontaneously replace a small number of HCs after damage, by conversion of non-sensory supporting cells (SCs) into HCs without an intervening cell division. The long-term goal of our research is to develop biologically based methods to replace lost HCs, in order to improve the quality of life of human patients. An understanding of HC and SC population dynamics in adult mammals under normal conditions is needed to achieve this goal. It is generally assumed that HCs are not added to the vestibular epithelia of mature mammals unless damage occurs. However, indirect evidence from several laboratories suggests vestibular HCs in adult rodents undergo turnover (removal and replacement) in the absence of damage. For example, both differentiating and dying HCs have been detected in the normal (undamaged) vestibular epithelia of adult bats and rodents. If vestibular HCs are continuously replaced in adult mammals, this plasticity would have major implications for HC homeostasis, HC loss during aging, and HC regeneration after damage. The proposed research will directly test the hypothesis that vestibular HCs undergo turnover in normal adult mice. In Aim 1, we will determine if vestibular HCs are dying and if so, define the position, number, and types that are dying. We will also assess if SCs act as phagocytes to clear HC debris. In Aim 2, we will use transgenic and knock-in mice to determine if new HCs are added to mouse vestibular epithelia under normal conditions. By tracing the fate of SCs and HCs, we will test the hypotheses that SCs transdifferentiate into type II HCs and type II HCs later convert into type I HCs. We will also determine if SCs are renewed by cell division. In Aim 3, we will determine if the rates of ongoing HC death and addition are altered with aging. In Aim 4, we will assess if the rate of SC-to-HC transdifferentiation is altered after near-complete HC destruction. This research project will help to characterize the natural mechanisms for HC replacement present in the vestibular epithelia of young and aged adult mice, which can be exploited to develop better therapies for balance disorders in the near future.

描述（由申请人提供）：许多美国人患有前庭功能障碍，这可以降低生活质量并增加跌倒和过早死亡的风险。前庭功能障碍的主要原因是毛细胞（HCS）的丧失，它会将头部运动转移到神经信号中，并使我们能够保持凝视，方向和控制身体运动。前庭HCS因耳毒性药物治疗，内耳感染以及与衰老相关的变化而死亡。在哺乳动物中，前庭HC在历史上被认为是不可替代的，因为许多与HC损失相关的症状都是永久性的。但是，一些研究表明，损坏后成年啮齿动物可以自发​​地替换少量的HC，通过将非感官支持细胞（SC）转化为HCS，而无需介入细胞分裂。我们研究的长期目标是开发基于生物学的方法来替代丢失的HC，以改善人类患者的生活质量。在正常情况下，需要了解成年哺乳动物的HC和SC人群动态以实现这一目标。通常认为，除非发生损害，否则不会将HCS添加到成熟哺乳动物的前庭上皮。但是，来自几个实验室的间接证据表明，在没有损害的情况下，成年啮齿动物中的前庭HC会经历营业额（去除和替换）。例如，在成年蝙蝠和啮齿动物的正常（未损坏）前庭上皮中都检测到了分化和垂死的HC。如果前庭HC在成年哺乳动物中连续替换，则这种可塑性将对HC稳态，衰老期间的HC损失和损害后HC再生产生重大影响。拟议的研究将直接检验以下假设：前庭HCS在正常成年小鼠中经历营业额。在AIM 1中，我们将确定前庭HC是否死亡，如果是的，则定义即将死亡的位置，数字和类型。我们还将评估SCS是否充当清除HC碎片的吞噬细胞。在AIM 2中，我们将使用转基因和敲入小鼠来确定在正常条件下是否将新的HC添加到小鼠前庭上皮中。通过追踪SCS和HCS的命运，我们将测试SCS转变为II型HCS的假设，然后将II型HCS转换为I型HCS。我们还将确定SC是否通过细胞分裂更新。在AIM 3中，我们将确定持续的HC死亡率和增加的衰老发生率是否改变。在AIM 4中，我们将评估近乎完整的HC破坏后SC-HC转分化的速率是否改变。该研究项目将有助于表征年轻和老年小鼠前庭上皮中存在的HC替代物的自然机制，可以利用这些机制在不久的将来开发出更好的平衡疾病疗法。