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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的前庭系统利用专门的毛细胞来感知重力和头部运动。前庭毛细胞大致分为两种细胞类型：I 型和 II 型。之间也存在明显的差异前庭器官的区域，由被毛细胞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之间存在差异，但人们对此知之甚少。现存的有证据表明，纹状体（中央）与纹状体外（外围）区域具有不同的功能，例如作为感应高频与低频的对比。这些功能差异是如何在分子水平上实现的不清楚。该提案的目的是表征不同毛细胞中的机械转导复合体和椭圆囊区域，这是一种前庭器官，对于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转导关键成分的转录本差异表达的数据复合体：跨膜通道样蛋白（TMC1 和 TMC2）。在斑马鱼和小鼠中，Tmc1 和 Tmc2 基因以与椭圆囊纹状体和纹状体外区域相关的区域梯度表达。我们的目标是确定 Tmc1/2 表达以及其他表达的动态发育和成人模式力转导复合体的成员。我们还打算将这些表达模式与头发相关联束形态和毛细胞生理学。此外，我们将检查 TMC 表达的这些特征和人类椭圆囊毛细胞中机械转导复合物的其他成分。确定范围物种间这些特征的保护对于动物模型的解释以及如何解释至关重要它们为前庭毛细胞的再生方法或其他前庭毛细胞治疗方法提供了信息人类患者的功能障碍。