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

• 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
• 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

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.

摘要。 生物体对其周围环境的感知取决于感官功能。神经感觉细胞 与听觉和平衡相关的关键生物过程有关。为了能够 这些细胞的功能依赖于一系列复杂的膜受体、离子通道， 信号分子集中在位于顶端的极其复杂的结构（毛发 细胞束和动纤毛）和基底（带状突触）极。例如，由于以下原因导致该网络中断 突变，导致形态和功能异常，并构成许多人类遗传学的基础 紊乱该提案的重点是研究Pcdh 15-Itga 8（原钙粘蛋白-15-整合素α 8）的作用。 毛细胞（HC）发育和功能过程中的复杂性，以及下游信号通路激活 了我们最近发表的工作和初步数据表明，Pcdh 15-Itga 8复合物结果的缺乏 在HC束异常中，外毛细胞数量增加，以及Rhoa-ERM（Ezrin-Radixin-Moesin）-雅普信号级联的改变。此外，Itga 8毛细胞特异性条件性敲除小鼠具有 进行性听力损失和对噪声暴露的敏感性。基于这些信息，我们的中心假设是 在内耳发育过程中，环境线索激活Itga 8-Pcdh 15复合体，导致内耳发育异常。 调节细胞骨架元件，激活下游信号级联。缺乏复杂性 导致内耳异常，随着时间的推移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Pcdh 15-Itga 8的环境线索 激活和细胞骨架结构的形成。我们还将识别和描述复杂的 分子靶点在第二个目标中，我们将研究支持细胞和螺旋神经节的贡献 Pcdh 15-Itga 8复合物表型和对噪声的敏感性。总体而言， 本文将阐明Pcdh 15-Itga 8复合物在Corti器官发育过程中的功能作用， 在Usher综合征和整合素下游信号级联之间引入直接的功能联系。