Role of XIRP2 in hair cell function and degeneration

XIRP2 在毛细胞功能和退化中的作用

基本信息

  • 批准号:
    9748086
  • 负责人:
  • 金额:
    $ 5.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-12-01 至 2019-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms that underlie the development, maintenance and degeneration of the mechanosensory hair bundle. Motivated by the fact that a third of all known deafness genes encode hair bundle proteins, we previously used a mass spectrometry based strategy to characterize the hair bundle proteome. This approach proved to be a powerful complement to traditional genetics strategies, leading to the discovery of novel deafness genes previously undetected using genetic strategies alone. For further analysis, we focused on proteins for which the corresponding gene locations overlap with unresolved human deafness loci. One such protein is XIRP2 (for xin actin-binding repeat containing protein 2). In this project, we are testing the hypothesis that XIRP2 is a novel hair cell protein required for long-term stability of stereocilia and the hair cell/supporting cell junctions, with the consequence that XIRP2 deficiency causes hair cell degeneration and progressive hearing loss. Preliminary studies demonstrated that different XIRP2 splice forms are present in the hair cell, displaying distinct localizations in the stereocilia and pericuticular adherens junctions, respectively. To explore the role of XIRP2 for hearing function, we used the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas technology to generate transgenic mice with a functional null mutation in the Xirp2 gene and found evidence for high-frequency hearing loss. In Specific Aim 1, we will investigate the hearing loss phenotype in Xirp2 null mice in detail. Furthermore, we will test whether XIRP2 deficiency renders the hair cell more sensitive to mechanical stress, by testing the sensitivity of Xirp2 null mice to noise-induced hearing loss. Preliminary studies suggested that the stereocilia and the adherens junctions harbor distinct XIRP2 isoforms, implying that defects in either hair cell structure could underlie the observed hearing loss in Xirp2 null mice. n Aim 2 and 3, we will therefore use transgenic mice with isoform specific deletions in the Xirp2 gene, to specifically address their contribution to hair cell degeneration and hearing loss. Our hypothesis that XIRP2 is required for long-term maintenance of hair cell structures dovetails well with its known role in cardiac muscle, where it is involved in the maintenance of the sarcomeric Z-line. XIRP2's role in the hair cell is likely to be distinct from and more complex than its functon in the heart: the hair bundle harbors a novel isoform with vastly different protein domain structure, rendering it practically an unknown protein. Significant for human hearing health, understanding the role of XIRP2 in hair cell degeneration is expected to shed light on mechanisms by which subtle defects caused by genetic and environmental factors can compromise the structural integrity of hair cell structures, significant for understanding the mechanistic basis of age and noise-induced hearing loss. Finally, the chromosomal locus of the XIRP2 gene overlaps with the human deafness loci DFNB27 and DFNA16, opening up the prospect of identifying the causative mutation for two human deafness phenotypes.
描述(由申请人提供):我们的长期目标是了解机械感觉毛束的发育、维持和退化的机制。受三分之一的已知耳聋基因编码毛束蛋白的事实,我们以前使用基于质谱的策略来表征毛束蛋白质组。这种方法被证明是对传统遗传学策略的有力补充,导致发现了以前单独使用遗传策略未发现的新耳聋基因。为了进一步分析,我们集中在蛋白质的相应基因位置与未解决的人类耳聋基因座重叠。一种这样的蛋白质是XIRP 2(对于含有蛋白质2的xin肌动蛋白结合重复)。在这个项目中,我们正在测试的假设,XIRP 2是一种新的毛细胞蛋白质所需的长期稳定的静纤毛和毛细胞/支持细胞连接,其结果是,XIRP 2缺乏导致毛细胞变性和进行性听力损失。初步研究表明,不同的XIRP 2剪接形式存在于毛细胞中,在毛细胞中显示出不同的定位。 静纤毛和表皮周粘连连接。为了探索XIRP 2对听力功能的作用,我们使用CRISPR(重复的规则间隔短回文重复序列)/Cas技术来产生在Xirp 2基因中具有功能无效突变的转基因小鼠,并发现高频听力损失的证据。在具体目标1中,我们将详细研究Xirp 2敲除小鼠的听力损失表型。此外,我们将通过测试Xirp 2缺失小鼠对噪声诱导的听力损失的敏感性来测试Xirp 2缺陷是否会使毛细胞对机械应力更敏感。初步研究表明,静纤毛和粘附连接具有不同的XIRP 2亚型,这意味着毛细胞结构的缺陷可能是Xirp 2基因敲除小鼠中观察到的听力损失的基础。因此,在目的2和3中,我们将使用在Xirp 2基因中具有同种型特异性缺失的转基因小鼠,以特异性地解决它们对毛细胞变性和听力损失的贡献。我们的假设,即XIRP 2是需要长期维护毛细胞结构的尾巴以及其已知的作用,在心肌中,它是在维护肌节Z线。XIRP 2在毛细胞中的作用可能与其在心脏中的功能不同,并且比其在心脏中的功能更复杂:毛束含有一种具有截然不同的蛋白质结构域结构的新型同种型,使其实际上是一种未知的蛋白质。对人类听力健康具有重要意义,了解XIRP 2在毛细胞变性中的作用有望揭示遗传和环境因素引起的细微缺陷可能损害毛细胞结构完整性的机制,这对于理解年龄和噪声引起的听力损失的机制基础具有重要意义。最后,XIRP 2基因的染色体位点与人类耳聋位点DFNB 27和DFNA 16重叠,为鉴定两种人类耳聋表型的致病突变开辟了前景。

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 }}

Jung-Bum Shin其他文献

Jung-Bum Shin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('Jung-Bum Shin', 18)}}的其他基金

Mechanosensor Proteins in Hair Cell Repair
毛细胞修复中的机械传感器蛋白
  • 批准号:
    10718860
  • 财政年份:
    2023
  • 资助金额:
    $ 5.55万
  • 项目类别:
Split-GFP tagging and live imaging of hair cell proteins
毛细胞蛋白的 Split-GFP 标记和实时成像
  • 批准号:
    10438419
  • 财政年份:
    2022
  • 资助金额:
    $ 5.55万
  • 项目类别:
Split-GFP tagging and live imaging of hair cell proteins
毛细胞蛋白的 Split-GFP 标记和实时成像
  • 批准号:
    10623203
  • 财政年份:
    2022
  • 资助金额:
    $ 5.55万
  • 项目类别:
Significance of Myo7a isoforms in hair cell function
Myo7a 亚型在毛细胞功能中的意义
  • 批准号:
    10032862
  • 财政年份:
    2020
  • 资助金额:
    $ 5.55万
  • 项目类别:
Significance of Myo7a isoforms in hair cell function
Myo7a 亚型在毛细胞功能中的意义
  • 批准号:
    10203919
  • 财政年份:
    2020
  • 资助金额:
    $ 5.55万
  • 项目类别:
Significance of Myo7a isoforms in hair cell function
Myo7a 亚型在毛细胞功能中的意义
  • 批准号:
    10466879
  • 财政年份:
    2020
  • 资助金额:
    $ 5.55万
  • 项目类别:
Significance of Myo7a isoforms in hair cell function
Myo7a 亚型在毛细胞功能中的意义
  • 批准号:
    10684263
  • 财政年份:
    2020
  • 资助金额:
    $ 5.55万
  • 项目类别:
Myosin 7a isoforms in functional diversity of cochlear hair cells
耳蜗毛细胞功能多样性中的肌球蛋白 7a 亚型
  • 批准号:
    9925302
  • 财政年份:
    2019
  • 资助金额:
    $ 5.55万
  • 项目类别:
Development of an AAV-CRISPR system for inner ear gene therapy
开发用于内耳基因治疗的 AAV-CRISPR 系统
  • 批准号:
    8765296
  • 财政年份:
    2014
  • 资助金额:
    $ 5.55万
  • 项目类别:
Role of XIRP2 in hair cell function and degeneration
XIRP2 在毛细胞功能和退化中的作用
  • 批准号:
    8957404
  • 财政年份:
    2014
  • 资助金额:
    $ 5.55万
  • 项目类别:

相似海外基金

A novel motility system driven by two classes of bacterial actins MreB
由两类细菌肌动蛋白 MreB 驱动的新型运动系统
  • 批准号:
    22KJ2613
  • 财政年份:
    2023
  • 资助金额:
    $ 5.55万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
The structural basis of plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
  • 批准号:
    342887
  • 财政年份:
    2016
  • 资助金额:
    $ 5.55万
  • 项目类别:
    Operating Grants
The structural basis for plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
  • 批准号:
    278338
  • 财政年份:
    2013
  • 资助金额:
    $ 5.55万
  • 项目类别:
    Operating Grants
Cytoplasmic Actins in Maintenance of Muscle Mitochondria
细胞质肌动蛋白在维持肌肉线粒体中的作用
  • 批准号:
    8505938
  • 财政年份:
    2012
  • 资助金额:
    $ 5.55万
  • 项目类别:
Differential Expression of the Diverse Plant Actins
多种植物肌动蛋白的差异表达
  • 批准号:
    7931495
  • 财政年份:
    2009
  • 资助金额:
    $ 5.55万
  • 项目类别:
Studies on how actins and microtubules are coordinated and its relevancy.
研究肌动蛋白和微管如何协调及其相关性。
  • 批准号:
    19390048
  • 财政年份:
    2007
  • 资助金额:
    $ 5.55万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
  • 批准号:
    6546977
  • 财政年份:
    2003
  • 资助金额:
    $ 5.55万
  • 项目类别:
Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
  • 批准号:
    6655612
  • 财政年份:
    2003
  • 资助金额:
    $ 5.55万
  • 项目类别:
Interaction of myosin with monomeric actins
肌球蛋白与单体肌动蛋白的相互作用
  • 批准号:
    5311554
  • 财政年份:
    2001
  • 资助金额:
    $ 5.55万
  • 项目类别:
    Priority Programmes
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
  • 批准号:
    6316669
  • 财政年份:
    2000
  • 资助金额:
    $ 5.55万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了