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The role of Eph/ephrin interactions in the development of inner ear innervation

Eph/ephrin 相互作用在内耳神经支配发育中的作用

基本信息

批准号：
BB/E002927/1
负责人：
Catherine Nobes
金额：
$ 43.14万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE002927%2F1
关键词：
role Eph ephrin interactions development

项目摘要

The inner ear is a highly complex architectural and functional structure that is exquisitely organised to detect sound and movement, yet it develops from a simple sheet of epithelial cells. During development this epithelium must generate and organise all of the major cell types found in the mature organ, including the specialised sensory hair cells that detect the sound or movement, the non-sensory cells that support sensory cell function and the neurones that connect the organ to the central nervous system. The sensory cells detect the sound or movement stimuli and convert these into signals that are sent to the central nervous system via neurones. It is only when these signals are processed in the brain that they are perceived as sound or movement. Thus, the development of the neuronal connection between the inner ear and the central nervous system is crucial to the function of the inner ear and the perception of sound and movement. The generation of neuronal precursors is an early event during the development of the inner ear. Within the simple epithelial sheet a population of cells begin to develop as neurones. They migrate out of the epithelium into the surrounding tissue where they coalesce to form the cochlear-vestibular ganglion. Subsequently, they produce processes that grow back into the epithelium to connect to the sensory hair cells and towards the auditory and vestibular centres in the central nervous system. These events require dynamic changes in the cell-cell interactions that drive their release from the epithelium, support their migration and direct the growth of processes to the correct targets. Cellular interactions are controlled by numerous cell surface molecules that send signals into the cell when they bind to surface partners (ligands) expressed by neighbouring cells. The cell signalling results in changes in cell behaviour by, for example, causing the cell to be attracted to, or repelled from, the source of the ligand. One such family of cell surface molecules are the Eph receptor tyrosine kinases (Ephs) and their ligands the ephrins. Interactions between these molecules have previously been shown to have important roles in the organisation of the nervous system but their role in the early development of inner ear innervation has yet to be investigated. The aim of the work proposed here is to better understand the role of Eph/ephrin interactions in the development of inner ear innervation. We will focus on two events: first, the migration of neuronal precursors out of the early inner ear epithelium and second, the early growth of neuronal processes. To address these questions we will further develop an otic epithelial explant system that is currently being used in the lab in order to allow manipulation of the expression of Ephs and ephrins. The effect of changing the expression of these molecules on neuroblast migration and process formation will then be monitored in culture using timelapse microscopy and immunohistochemistry. These experiments will further our understanding of neuronal development of the inner ear and other organs derived from epithelia, such as the olfactory system. The development of a novel technique to manipulate expression of important molecules within a developing organ in culture will facilitate future studies into the development of these organs. In addition, these experiments will aid research into nerve regeneration following damage and potentially influence the development of cochlear implants by elucidating potential strategies to encourage neural growth towards implant electrodes, thereby, enhancing the implant performance.

内耳是一个高度复杂的结构和功能结构，它被精巧地组织起来以检测声音和运动，但它是从一个简单的上皮细胞片发展而来的。在发育过程中，这种上皮细胞必须产生和组织成熟器官中发现的所有主要细胞类型，包括检测声音或运动的专门感觉毛细胞，支持感觉细胞功能的非感觉细胞以及将器官连接到中枢神经系统的神经元。感觉细胞检测声音或运动刺激，并将其转换为通过神经元发送到中枢神经系统的信号。只有当这些信号在大脑中被处理时，它们才被感知为声音或运动。因此，内耳和中枢神经系统之间的神经元连接的发展对于内耳的功能以及声音和运动的感知至关重要。神经元前体的产生是内耳发育过程中的早期事件。在简单的上皮层内，一群细胞开始发育为神经元。它们从上皮细胞迁移到周围组织中，在那里它们合并形成耳蜗前庭神经节。随后，它们产生生长回上皮的过程，以连接到感觉毛细胞并朝向中枢神经系统中的听觉和前庭中心。这些事件需要细胞-细胞相互作用的动态变化，以驱动它们从上皮释放，支持它们的迁移并将过程的生长引导到正确的靶点。细胞相互作用由许多细胞表面分子控制，当它们与相邻细胞表达的表面伴侣（配体）结合时，这些分子将信号发送到细胞中。细胞信号传导导致细胞行为的变化，例如，通过使细胞被吸引到配体的来源或从配体的来源排斥。一个这样的细胞表面分子家族是Eph受体酪氨酸激酶（Eps）及其配体肝配蛋白。这些分子之间的相互作用先前已被证明在神经系统的组织中具有重要作用，但它们在内耳神经支配的早期发育中的作用尚未被研究。本文提出的工作的目的是更好地理解Eph/ephrin相互作用在内耳神经支配发展中的作用。我们将集中在两个事件：第一，迁移的神经元前体细胞的早期内耳上皮和第二，早期生长的神经元过程。为了解决这些问题，我们将进一步开发目前在实验室中使用的耳上皮外植体系统，以允许操纵Ephs和ephrin的表达。改变这些分子的表达对成神经细胞迁移和过程形成的影响，然后将在培养中使用时移显微镜和免疫组织化学进行监测。这些实验将进一步加深我们对内耳和其他上皮器官（如嗅觉系统）神经元发育的理解。开发一种新的技术来操纵培养中发育器官内重要分子的表达，将促进未来对这些器官发育的研究。此外，这些实验将有助于研究损伤后的神经再生，并通过阐明鼓励神经向植入电极生长的潜在策略，从而提高植入性能，从而可能影响人工耳蜗植入物的发展。