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

抽象的。 有机体对周围环境的感知取决于感官功能。神经感觉细胞 来自内耳的蛋白质参与与听力和平衡相关的关键生物学过程。为了能够 这些细胞依靠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(毛发)的极其复杂的结构中 细胞束和动纤毛)和基极(带状突触)。例如，由于以下原因导致此网络中断 突变，导致形态和功能异常，并形成许多人类基因的基础 精神错乱。这项建议的重点是研究PCDH15-Itga8(原钙粘蛋白-15-整合素α8)的作用。 毛细胞(HC)发育和功能过程中的复杂性，以及下游信号通路由 它。我们最近发表的工作和初步数据表明，PCDH15-Itga8的缺乏复杂的结果 在HC束异常中，外毛细胞数量增加，Rhoa-ERM(Ezrin-Radioxin-Moesin)-YAP信号级联改变。此外，Itga8毛细胞特异性条件性基因敲除小鼠 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 在内耳发育期间，环境线索激活了Itga8-PCDH15复合体，导致 细胞骨架元件的调制将激活下游信号级联反应。缺乏情结 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 有两个明确的目标。在第一个目标中，我们将确定导致PCDH15-Itga8的环境线索 细胞骨架结构的激活和形成。我们还将确定和描述该建筑群的 分子靶标。在第二个目标中，我们将研究支持细胞和螺旋神经节的作用 神经元对PCDH15-Itga8复合体的表型和对噪声的敏感性。总而言之，这些研究建议 这里将阐明PCDH15-Itga8复合体在Corti器官发育中的功能作用(S)， 引入了Usher综合征和整合素下游信号级联之间的直接功能联系。

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.