Identification and characterization of novel functions for the Usher proteins in the inner ear

内耳 Usher 蛋白新功能的鉴定和表征

基本信息

批准号：
10677948
负责人：
Marisa L. Zallocchi
金额：
$ 52.01万
依托单位：
CREIGHTON 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：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677948
关键词：
Address Adult Affect American Animals Apical Architecture Biological Process Biomechanics Blindness COVID-19 pandemic Cell Maturation Cell physiology Cells Cochlea Communities Complex Cues Cytoskeleton Data Defect Deposition Development Disease Disease Progression Ear Elements Environment Equilibrium Extracellular Matrix Fishes Genetic Genetic Diseases Hair Cells Hearing High-Frequency Hearing Loss Human Genetics Integrin alpha Chains Integrins Ion Channel Kinocilium Knockout Mice Laboratories Labyrinth Link Membrane Molecular Molecular Target Morphology Mus Mutation Neurons Noise Organ Organ of Corti Organism Outer Hair Cells PCDH15 gene Pathology Pathway interactions Perception Phenotype Photoreceptors Positioning Attribute Proteins Publishing Retina Retinitis Pigmentosa Role Sensory Signal Pathway Signal Transduction Signaling Molecule Social Distance Structure Supporting Cell Testing Time Tissues Touch sensation Usher Proteins Usher Syndrome Work Zebrafish base cell type conditional knockout deaf deafness defined contribution ezrin hearing impairment inner ear development mature animal moesin mutant neurosensory noise exposure novel progressive hearing loss protein activation radixin protein receptor ribbon synapse sensor small molecule spiral ganglion temporal measurement transcriptome sequencing

项目摘要

ABSTRACT. An organism’s perception of its surrounding environment depends on the sensory function. Neurosensory cells from the inner ear are involved in key biological processes associated with hearing and balance. To be able to achieve their function these cells depend on a complex array of membrane receptors, ion channels, and signaling molecules that are concentrated at extremely sophisticated structures positioned at the apical (hair cell bundle and kinocilium) and basal (ribbon synapses) poles. Disruption of this network due, for example, to mutations, results in morphological and functional abnormalities and forms the bases of many human genetic disorders. This proposal is focused on studying the role of the Pcdh15-Itga8 (Protocadherin-15-Integrin alpha8) complex during hair cell (HC) development and function, and the downstream signaling pathways activated by it. Our recently published work and preliminary data suggest that the absence of Pcdh15-Itga8 complex results in HC bundle abnormalities, increase the number of outer hair cells, and alterations in the Rhoa-ERM(Ezrin-Radixin-Moesin)-Yap signaling cascade. Moreover, Itga8 hair cell-specific conditional knockout mice have progressive hearing loss and sensibility to noise exposure. Based on this information, our central hypothesis is that during inner ear development, environmental cues activate the Itga8-Pcdh15 complex resulting in the modulation of cytoskeletal elements that will activate downstream signaling cascades. Lack of the complex results in inner ear abnormalities that over time can cause progressive hearing loss. We will test this hypothesis with two specific aims. In the first aim, we will identify the environmental cues that lead to Pcdh15-Itga8 activation and the formation of cytoskeletal structures. We will also identify and characterize the complex’s molecular targets. In the second aim, we will investigate the contribution of supporting cells and spiral ganglion neurons to the Pcdh15-Itga8 complex phenotype and the sensibility to noise. Collectively the studies proposed here will clarify the functional role(s) for the Pcdh15-Itga8 complex during organ of Corti development, introducing a direct functional link between Usher syndrome and an integrin-downstream signaling cascade.

抽象的。生物体对其周围环境的感知取决于感觉神经细胞的功能。来自内耳的参与与听力和平衡相关的关键生物过程。这些细胞实现其功能依赖于一系列复杂的膜受体、离子通道和信号分子集中在位于顶端（头发例如，由于细胞束和运动纤毛）和基底（带状突触）极的破坏。突变，导致形态和功能异常，并构成许多人类遗传学的基础该提案的重点是研究 Pcdh15-Itga8（Protocadherin-15-Integrin alpha8）的作用。毛细胞（HC）发育和功能过程中的复合体，以及由毛细胞（HC）激活的下游信号通路我们最近发表的工作和初步数据表明缺乏 Pcdh15-Itga8 复合物结果。 HC 束异常、外毛细胞数量增加以及 Rhoa-ERM(Ezrin-Radixin-Moesin)-Yap 信号级联的改变此外，Itga8 毛细胞特异性条件性基因敲除小鼠也有这种现象。根据这些信息，我们的中心假设是进行性听力损失和对噪音暴露的敏感性。在内耳发育过程中，环境信号激活 Itga8-Pcdh15 复合物，从而导致将激活下游信号级联的细胞骨架元件的调节缺乏复合物。导致内耳异常，随着时间的推移，可能会导致进行性听力损失，我们将检验这一假设。有两个具体目标在第一个目标中，我们将确定导致 Pcdh15-Itga8 的环境线索。我们还将鉴定和表征该复合物的激活和细胞骨架结构的形成。在第二个目标中，我们将研究支持细胞和螺旋神经节的贡献。神经元对 Pcdh15-Itga8 复合体表型的影响以及对噪声的敏感性。这里将阐明 Pcdh15-Itga8 复合物在 Corti 器官发育过程中的功能作用，介绍了 Usher 综合征和整合素下游信号级联之间的直接功能联系。