Diversification of the mechanotransduction complex in vestibular hair cells

前庭毛细胞中机械转导复合体的多样化

• 批准号: 10734358
• 负责人: Alan Gi-Lun Cheng
• 金额: $ 65.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734358
• 关键词: Adolescent; Adult; Animal Model; Architecture; Behavior; Behavioral; Behavioral Assay; Calcium; Caring; Cell physiology; Cells; Cellular Morphology; Characteristics; Cochlea; Comparative Study; Complex; Coupled; Data; Defect; Development; Dizziness; Dyes; Electrophysiology (science); Evoked Potentials; Evolution; Eye Movements; Fishes; Foundations; Frequencies; Functional disorder; Future; Genes; Genetic Transcription; Gravity Perception; Hair; Hair Cells; Head; Human; Ion Channel; Label; Labyrinth; Larva; Link; Mammals; Mediating; Medical; Membrane; Methods; Molecular; Molecular Profiling; Morphology; Motion; Mus; Mutant Strains Mice; Natural regeneration; Organ; Organ Donor; Outer Hair Cells; PCDH15 gene; Patients; Pattern; Peripheral; Physiological; Physiology; Protein Isoforms; Proteins; RNA; Reflex action; Regulation; Role; Sensory; Sensory Hair; Stimulus; Study models; System; Testing; Therapeutic; Tissue Donors; Transcript; Type II Hair Cell; Utricle structure; Validation; Vertigo; Vestibular Hair Cells; Work; Zebrafish; cell type; differential expression; experimental study; hair cell regeneration; in vivo; insight; link protein; live cell imaging; mechanotransduction; member; mouse model; mutant; nerve supply; older patient; response; single cell analysis; single-cell RNA sequencing; sound; spatiotemporal; vestibular reflex; vibration

Abstract The vestibular system utilizes specialized hair cells for sensing gravity and head motions. Vestibular hair cells have been broadly characterized into two cell types: Type I and Type II. Clear differences also exist among the zones of vestibular organs, consisting of a central zone surrounded by a peripheral zone of hair cells. How the mechanotransduction machinery varies across these two cell types or zones is poorly understood. Existing evidence suggests that the striolar (central) versus extrastriolar (peripheral) zones serve different functions such as sensing high versus low frequencies. How these functional differences are achieved at the molecular level is not clear. The aim of this proposal is to characterize the mechanotransduction complex in the different hair cells and zones of the utricle, a vestibular organ that is vital for sensing gravity and head motions. We have preliminary data that demonstrate differential expression of transcripts encoding a key component of the mechanotransduction complex: transmembrane channel-like proteins (TMC1 and TMC2). In zebrafish and the mouse, both Tmc1 and Tmc2 genes are expressed in regional gradients that correlate with the striolar and extrastriolar zones of the utricle. We aim to determine the dynamic developmental and adult patterns of Tmc1/2 expression along with other members of the mechanotransduction complex. We also intend to correlate these expression patterns with hair bundle morphology and hair cell physiology. In addition, we will examine these features of TMC expression and other components of the mechanotransduction complex in human utricular hair cells. Determining the extent of conservation of these features among species will be essential for the interpretation of animal models and how they inform approaches to regeneration of vestibular hair cells or other therapeutic methods for vestibular dysfunction in human patients.

摘要 前庭系统利用专门的毛细胞来感知重力和头部运动。前庭毛细胞 已经被广泛地表征为两种细胞类型：I型和II型。也存在明显的差异， 前庭器官的区域，由毛细胞的外围区域包围的中心区域组成。如何 机械转导机制在这两种细胞类型或区域中的变化知之甚少。现有 有证据表明，纹状体（中央）与纹状体外（外周）区具有不同的功能， 感知高频和低频的区别如何在分子水平上实现这些功能差异， 不清楚该建议的目的是表征不同毛细胞中的机械转导复合物 以及椭圆囊的区域，椭圆囊是一种前庭器官，对感知重力和头部运动至关重要。我们有初步的 证明编码机械传导的关键组分的转录物的差异表达的数据 复合物：跨膜通道样蛋白（TMC 1和TMC 2）。在斑马鱼和小鼠中，Tmc 1和 tmc 2基因表达的区域梯度与胞囊的纹状带和纹外带相关。 我们的目的是确定Tmc 1/2表达的动态发育和成人模式，以及其他沿着的表达。 机械传导复合体的成员。我们还打算将这些表达模式与毛发 束形态学和毛细胞生理学。此外，我们将研究TMC表达的这些特征， 人类椭圆囊毛细胞中机械传导复合物的其他成分。确定的程度 在物种之间保存这些特征对于解释动物模型以及如何解释动物模型是至关重要的。 它们为前庭毛细胞的再生或前庭神经损伤的其他治疗方法提供了信息。 人类患者的功能障碍。