Genetic Regulation of Cochlear Development

耳蜗发育的基因调控

• 批准号: 8022888
• 负责人: Andrew K Groves
• 金额: $ 44.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022888
• 关键词: Appearance; Biological Assay; Bone Morphogenetic Proteins; Cell Death; Cells; Cochlea; Cochlear duct; Data; Development; Embryo; Enzymes; Family; Fucosyltransferase; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Hair Cells; Hearing; Human; Image; In Vitro; Individual; Inherited; Inner Hair Cells; Labyrinth; Length; Ligands; Light; Mammals; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Natural regeneration; Nature; Notch Signaling Pathway; Organ; Organ Culture Techniques; Organ of Corti; Pathway interactions; Pattern; Phenotype; Play; Production; Protein Family; Regulation; Research Personnel; Role; Running; Sensorineural Hearing Loss; Sensory; Sensory Hair; Side; Signal Pathway; Signal Transduction; Specific qualifier value; Supporting Cell; System; Technology; Testing; Time; Tissues; To specify; Transgenic Mice; Work; assay development; base; cell type; deafness; fringe protein; glycosyltransferase; hearing impairment; human MFNG protein; jagged1 protein; loss of function; member; morphogens; mutant; notch protein; novel; prevent; public health relevance; receptor; relating to nervous system; research study; response

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.

描述（由申请人提供）：Corti器官是哺乳动物耳蜗的一种感觉专门化器官，它调节我们的听觉。了解Corti的器官是如何发育的，可能会对某些遗传性耳聋的基础有所帮助。它还可以帮助那些耳蜗感觉细胞被破坏的个体再生这些细胞，这是一种被称为感觉神经性听力损失的常见情况。Corti的器官来源于沿胚胎耳蜗导管长度运行的细胞的前感觉结构域，但诱导该结构域的分子信号的性质存在争议。一些研究表明Notch信号通路诱导前感觉结构域，但我们自己使用Notch信号缺陷小鼠进行的初步实验并不支持这一观点。相反，我们认为骨形态发生蛋白（Bone Morphogenetic Protein， BMP）信号可以诱导前感觉区域，也可以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Fringe家族相互作用来定义Corti器官的边界。这项提议的目标是识别诱导前感觉区域和Corti器官的信号，并正确地将模式信息传递给耳蜗管，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的Notch信号通路缺陷的基因工程小鼠品系来确定在没有Notch信号的情况下，前感觉结构域和Corti器官是否正常发育。其次，我们将使用BMP信号通路有缺陷的小鼠，并检查耳蜗的发育。我们还将测试将胚胎耳蜗暴露在不同浓度的BMP中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该边界在正常Corti器官发育中的重要性。