Genetic Regulation of Cochlear Development

描述(申请人提供)：科尔蒂器官是哺乳动物耳蜗的感官特化，调节我们的听觉。了解Corti器官是如何发育的，可能会对某些遗传性耳聋的基础有所帮助。它还可能有助于尝试在耳蜗感觉细胞被破坏的情况下再生这些细胞--这种常见的情况被称为感觉神经性听力损失。Corti器官来自于一个与胚胎耳蜗管一样长的细胞的前感觉域，但诱导这个域的分子信号的性质存在争议。几项研究表明，Notch信号通路诱导前感觉域，但我们自己使用Notch信号缺陷小鼠的初步实验不支持这一想法。相反，我们认为，骨形态发生蛋白(BMP)信号诱导前感觉域，也可能以浓度依赖的方式诱导Corti器官两侧的非感觉区域。然而，我们不排除Notch信号在耳蜗发育中的作用，因为我们的数据表明，Notch信号可能通过与Notch修饰酶的边缘家族相互作用来定义Corti器官的边界。这项建议的目标是识别诱导前感觉区和Corti器官的信号，并正确地将构图信息传递给耳蜗管，以便在正确的时间在正确的位置形成正确的细胞类型。我们将通过三种不同的方法来实现我们的目标。首先，我们将使用两种不同品系的基因工程小鼠，在这些小鼠中，Notch信号通路存在缺陷，以确定在没有Notch信号的情况下，Corti的感觉域和器官是否正常发育。其次，我们将使用BMP信号通路缺陷的小鼠，并检查耳蜗组织的发育。我们还将测试将不同浓度的BMP暴露于不同的胚胎耳蜗片是否可以诱导不同类型的耳蜗细胞分化。最后，我们将使用我们认为无法在Corti器官和耳蜗周围部分之间形成正常边界的基因工程小鼠来检查这一边界在Corti正常器官发育中的重要性。 与公共健康相关：这项提案旨在了解哺乳动物耳蜗体是如何发育的。由于耳蜗负责人类的听力，我们相信我们的工作将有助于我们了解某些形式的遗传性听力损失的基础。它还可能建议如何在听力丧失的人身上重新种植受损的耳蜗区。

DESCRIPTION (provided by applicant): The organ of Corti is a sensory specialization of the mammalian cochlea that mediates our sense of hearing. Understanding how the organ of Corti develops may shed light on the basis of certain inherited forms of deafness. It may also help attempts to regenerate the sensory cells of the cochlea in individuals where these cells have been destroyed - a common condition known as sensorineural hearing loss. The organ of Corti derives from a prosensory domain of cells running the length of the embryonic cochlear duct, but the nature of the molecular signals that induce this domain are controversial. Several studies suggest that the Notch signaling pathway induces the prosensory domain, but our own preliminary experiments using mice defective in Notch signaling do not support this idea. Instead, we suggest that Bone Morphogenetic Protein (BMP) signaling induces the prosensory domain and may also induce the non-sensory regions on either side of the organ of Corti in a concentration-dependent fashion. We do not rule out a role for Notch signaling in the developing cochlea however, as our data suggest that Notch signaling may define the boundaries of the organ of Corti by interacting with the Fringe family of Notch-modifying enzymes. The goals of this proposal are to identify the signals that induce the prosensory domain and the organ of Corti, and that correctly impart patterning information to the cochlear duct so that the right cell types are formed in the right place at the right time. We will accomplish our goals with three different approaches. First, we will use two different strains of genetically engineered mice in which the Notch signaling pathway is defective to determine whether the prosensory domain and the organ of Corti develop correctly without Notch signals. Second, we will use mice in which the BMP signaling pathway is defective, and examine the development of the cochlea. We will also test whether exposing pieces of embryonic cochlea to different concentrations of BMP can induce different cochlear cell types to differentiate. Finally, we will use genetically engineered mice that we believe will be unable to form a normal boundary between the organ of Corti and surrounding parts of the cochlea to examine the importance of this boundary in normal organ of Corti development. PUBLIC HEALTH RELEVANCE: This proposal aims to understand how the cochlea develops in mammals. Since the cochlea is responsible for human hearing, we believe that our work will help us understand the basis of some forms of hereditary hearing loss. It may also suggest ways to re-grow damaged parts of the cochlea in individuals who have lost their hearing.