Functional Development of Hair Cells

毛细胞的功能发育

基本信息

批准号：
9319225
负责人：
Gwenaelle S Geleoc
金额：
$ 36.98万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319225
关键词：
Adult Alleles Auditory Automobile Driving Behavioral Biological Assay Biological Models Biophysics Cell Survival Cell physiology Cochlea Code Complex Development Engineering Functional disorder Gene Expression Gene Family Generations Genes Genomics Grant Hair Hair Cells Hearing Impaired Persons Human Inner Hair Cells Knock-in Knock-in Mouse Knockout Mice Labyrinth Life Maintenance Mammals Mechanical Stimulation Modeling Molecular Morphology Mus Mutant Strains Mice Mutation Organ of Corti Outer Hair Cells Paper Partner in relationship Pattern Phenotype Physiological Property Proteins Role Sensorineural Hearing Loss Sensory Sensory Hair Site System Technology Terminator Codon Time Transgenic Mice Transgenic Model Work base cellular transduction deafness design direct application gene function hearing impairment inducible gene expression mRNA Expression mechanotransduction member mouse model novel paralogous gene postnatal promoter protein expression public health relevance recombinase-mediated cassette exchange response tool

项目摘要

DESCRIPTION (provided by applicant): Mutations in the transmembrane cochlear expressed gene 1 (TMC1) underlies dominant progressive hearing loss (DFNA36) and recessive nonsyndromic sensorineural hearing loss deafness (DFNB7/B11) (Kurima et al., 2002). Similarly, semidominant and recessive alleles of Tmc1 cause hearing loss in Beethoven (Bth) and Deafness (dn) mutant mice (Vreugde et al.,2002; Kurima et al., 2002). Tmc1 is a member of the Tmc gene family that includes seven other paralogs in mammals (Keresztes et al., 2003). Tmc1 and Tmc2 are expressed in hair cells of the inner ear. We have recently demonstrated that mice that lack Tmc1 and Tmc2 are deaf and suffer profound vestibular dysfunction. Interestingly, analysis of Tmc1 and Tmc2 mRNA expression during organ of Corti development revealed a tonotopic expression pattern and a developmental switch from Tmc2 to Tmc1 (Kawashima, G�l�oc et al. 2011). The rise of Tmc2 mRNA expression coincided with the developmental acquisition of hair cell transduction. Analysis of transduction currents in cochlear outer hair cells of mice lacking Tmc1 or Tmc2 revealed nearly normal responses during the first postnatal week. On the other hand, hair cells from double knockout mice that lacked Tmc1 and Tmc2 did not respond to mechanical stimulation at any time point during development or in any region along the organ of Corti despite the presence of normal hair bundle morphology. Based on these observations we hypothesize that Tmc1 and Tmc2 have redundant functions and that expression of either Tmc1 or Tmc2 is required for hair cell mechanotransduction. Since Tmc2 expression is transient during the first postnatal week, the developmental switch to Tmc1 at the end of the first postnatal week could explain the deafness phenotype associated with mutations in Tmc1 in mice and humans. To explore the temporal constraints of Tmc1 and Tmc2 expression, the developmental switch in expression and their functional redundancy, we will generate several novel mouse models with conditional deletion, conditional expression and inducible expression of Tmc1 and Tmc2 and assay for changes in the properties of mechanotranduction and auditory function.

描述（由申请人提供）：跨膜耳蜗表达基因 1 (TMC1) 的突变是显性进行性听力损失 (DFNA36) 和隐性非综合征性感音神经性听力损失耳聋 (DFNB7/B11) 的基础 (Kurima 等人，2002)。 Tmc1 的隐性等位基因导致贝多芬 (Bth) 听力损失和耳聋(dn) 突变小鼠（Vreugde 等人，2002 年；Kurima 等人，2002 年）。我们最近证明，缺乏 Tmc1 和 Tmc2 的小鼠会耳聋并患有严重的前庭功能障碍。神秘的是，对 Corti 器官发育过程中 Tmc1 和 Tmc2 mRNA 表达的分析揭示了音调表达模式和从 Tmc2 到 Tmc1 的发育转换（Kawashima，G�l�oc 等人，2011）。Tmc2 mRNA 表达的上升是一致的。对缺乏 Tmc1 或 Tmc2 的小鼠耳蜗外毛细胞的转导电流的分析显示，在发育过程中，反应几乎正常。另一方面，尽管存在正常的发束形态，但缺乏 Tmc1 和 Tmc2 的双基因敲除小鼠的毛细胞在发育过程中的任何时间点或柯蒂氏器官的任何区域都没有对机械刺激做出反应。基于这些观察，我们认为 Tmc1 和 Tmc2 具有冗余功能，并且 Tmc1 或 Tmc2 的表达是毛细胞机械转导所必需的，因为 Tmc2 表达在第一个过程中是瞬时的。出生后第一周结束时向 Tmc1 的发育转变可以解释与小鼠和人类 Tmc1 突变相关的耳聋表型。探索 Tmc1 和 Tmc2 表达的时间限制、表达的发育转变及其功能。由于冗余，我们将生成几种具有 Tmc1 和 Tmc2 条件删除、条件表达和诱导表达的新型小鼠模型，并测定机械传导和听觉功能特性的变化。