ACTIVITY-DRIVEN PLASTICITY OF THE HAIR CELL CYTOSKELETON

活动驱动的毛细胞细胞骨架的可塑性

基本信息

  • 批准号:
    10748106
  • 负责人:
  • 金额:
    $ 44.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-07 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The mechanosensitivity of the inner ear hair cells depends on cellular projections known as stereocilia, organized in rows of increasing height, with mechano-electrical transduction (MET) channels located at the tips of shorter row stereocilia. The core of stereocilia consists of a highly crosslinked paracrystalline array of actin filaments. While crosslinker proteins are constantly renewed, the renewal of actin is limited to the stereocilia tips. We previously reported that the stereocilia actin core exhibits activity-dependent plasticity (Velez-Ortega, et al., eLife 2017). We showed that the blockage of MET channels or the breakage of the tip links that gate these channels lead to the selective shortening of transducing stereocilia (i.e. the stereocilia that harbor MET channels), while the non-transducing tallest row stereocilia remain unaffected. Once the MET blockage is removed or the tip links regenerate, the stereocilia regrow. Our preliminary data also show that this MET-dependent stereocilia remodeling can affect the resting tension within the MET machinery in seconds. Thus, this process may dynamically regulate the sensitivity of hair cells to sound-induced vibrations and, hence, the sensitivity of our hearing. Yet, the exact mechanisms of MET-dependent stereocilia remodeling are still obscure. It is unknown even whether the activity-dependent plasticity of the stereocilia cytoskeleton is limited to the regions of active actin renewal or can expand beyond this region into the “stable” part of the stereocilia shaft. Here, we hypothesize that the MET activity regulates the extent of the stereocilia cytoskeleton undergoing active actin remodeling. To test this, Aim 1 will evaluate MET-dependent changes in actin dynamics within the stereocilia and the cuticular plate, an actin-rich structure supporting the stereocilia bundle. Aim 2 will evaluate MET-driven changes in the ultrastructural organization of stereocilia actin with transmission electron microscopy tomography. Since the MET-dependent stereocilia remodeling was studied so far only in young postnatal hair cells, Aim 3 will assess whether this phenomenon is present also in the mature adult auditory hair cells. In Aim 4, we begin to explore the molecular players involved in the MET-driven stereocilia remodeling, by evaluating the expression of so-called “stereocilia row identity proteins” in a mutant mouse model that exhibits MET-dependent actin remodeling not only in transducing stereocilia but also, unexpectedly, in non-transducing stereocilia. The study is significant, because it may clarify how exactly a hair cell performs fine adjustments of the architecture of the stereocilia bundle, thereby maintaining the sensitivity of our hearing throughout a lifetime. In addition, stereocilia shortening—and perhaps their eventual disappearance—could occur after noise exposure (when the MET current is reduced due to tip link breakage) or in certain cases of congenital deafness (due to impaired MET current). Therefore, this study will expand our knowledge of the molecular mechanisms of various types of hearing loss.
项目总结/摘要 内耳毛细胞的机械敏感性取决于细胞投射, 静纤毛,排列成行,高度逐渐增加,具有机械-电转换(MET)通道 位于短列静纤毛顶端。静纤毛的核心由高度交联的 肌动蛋白丝的准晶体排列。虽然交联剂蛋白质不断更新, 肌动蛋白仅限于静纤毛尖端。我们先前报道了静纤毛肌动蛋白核心表现出活性依赖性可塑性(Velez-Ortega等人,eLife 2017)。我们发现MET通道的阻塞 或门控这些通道的尖端连接的断裂导致转导的选择性缩短, 静纤毛(即,具有MET通道的静纤毛),而非转导最高行静纤毛 不受影响。一旦MET阻塞被移除或尖端链接再生,静纤毛再生。 我们的初步数据还表明,这种MET依赖的静纤毛重塑可以影响静息的 金属爆炸装置的张力因此,该过程可以动态地调节灵敏度 毛细胞对声音引起的振动的敏感性,因此,我们的听觉的敏感性。然而, MET依赖性静纤毛重塑的机制仍然不清楚。目前还不清楚, 静纤毛细胞骨架的活性依赖性可塑性仅限于活跃的肌动蛋白更新区域 或者可以扩张超过该区域进入静纤毛轴的“稳定”部分。在这里,我们假设, MET活性调节静纤毛细胞骨架经历主动肌动蛋白重塑的程度。 为了验证这一点,Aim 1将评估静纤毛内肌动蛋白动力学的MET依赖性变化, 角质板,支持静纤毛束的富含肌动蛋白的结构。目标2将评估MET驱动 静纤毛肌动蛋白超微结构的变化 断层扫描由于MET依赖的静纤毛重塑迄今为止仅在年轻的出生后研究 Aim 3将评估这种现象是否也存在于成熟的成年听毛中 细胞在目标4中,我们开始探索参与MET驱动的静纤毛的分子参与者 重塑,通过评估突变小鼠中所谓的“静纤毛行同一性蛋白”的表达, 模型显示MET依赖的肌动蛋白重塑不仅在转导静纤毛, 出乎意料地,在非转导静纤毛中。这项研究意义重大,因为它可能会阐明 毛细胞对静纤毛束的结构进行精细的调整,从而维持 听觉的灵敏度。此外,静纤毛缩短,也许他们的 最终消失-可能发生在噪声暴露后(当MET电流由于尖端而降低时 连接断裂)或在某些先天性耳聋的情况下(由于受损的MET电流)。因此本 这项研究将扩大我们对各种类型听力损失的分子机制的认识。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Alejandra Catalina Velez Ortega其他文献

Alejandra Catalina Velez Ortega的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Alejandra Catalina Velez Ortega', 18)}}的其他基金

Supplement for Mechanotransduction-Dependent Remodeling of the Stereocilia Cytoskeleton
立体纤毛细胞骨架的机械传导依赖性重塑的补充
  • 批准号:
    10170923
  • 财政年份:
    2018
  • 资助金额:
    $ 44.2万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
  • 批准号:
    10065645
  • 财政年份:
    2023
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 44.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了