DISSECTING THE EAR NEUROSENSORY DEVELOPMENT.

剖析耳朵神经感觉发育。

• 批准号: 7145833
• 负责人: BERND FRITZSCH
• 金额: $ 36.64万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145833
• 关键词: afferent nerve; biological signal transduction; brain derived neurotrophic factor; cell cell interaction; developmental genetics; developmental neurobiology; ear hair cell; epithelium; gene expression; genetically modified animals; growth factor receptors; immunocytochemistry; in situ hybridization; innervation; intermolecular interaction; laboratory mouse; labyrinth; neurogenesis; neurogenetics; neurons; neurotrophic factors; polymerase chain reaction; receptor expression

DESCRIPTION (provided by applicant): The neurosensory components of the ear that extract vestibular and auditory information and conduct it to the brain are hair cells and sensory neurons. Our short term goal is to analyze in vivo the molecular biology of neurosensory cell formation and survival that generates the most crucial cell types of the ear and connects them. Our long term goal is to use this information for neurosensory regeneration and to guide growing afferents to reach either regenerated hair cells or stimulating electrodes of cochlear implants. We will focus in this application on three steps required to develop and connect hair cells and sensory neurons. These are neurosensory fate determination, neurosensory fate acquisition and neurosensory connection formation. All of these events are influenced by a cascade of genes expressed in the growing otocyst. We will concentrate on the role of three genes and their possible interactions that determine the neurosensory region of the ear using composite mutant mice that are null or heterozygous for various combinations of three genes (Aim1). We will continue our investigation on the role of the three major bHLH genes in various combinations that are null or heterozygous or in newly generated transgenic line to dissect the molecular mechanisms of hair cell and sensory neuron fate acquisition (Aim2). Aim3 will extend our investigations into neonates and postnatal mice on the role of neurotrophins for neuronal fiber guidance through the use of transgenic misexpression and targeted elimination of neurotrophins in the ear. AIM 1 will specify the role of FgflO, Gata3 and Foxgl in neurosensory development of the ear. These three factors are known to interact in neurosensory development in the central and peripheral nervous systems of mice and flies, but their interactions in the ear are not clarified. AIM 2 will test the molecular interactions of bHLH genes (Atohl, Neurogl, Neurodl) in hair cell and sensory neuron development. Identifying multipotent precursors, that can be manipulated to generate all neurosensory cells could greatly benefit current attempts of restoring neurosensory hearing loss. AIM 3 will molecularly dissect the role of neurotrophins in neonatal and postnatal fiber reorganization using conditional Bdnf ear mutations in combination with transgenic misexpressors. Such information is crucial to govern the use of neurotrophins for regeneration, plasticity and maintenance of adult innervation.

描述（由申请人提供）：提取前庭和听觉信息并将其传导至大脑的耳朵的神经感觉成分是毛细胞和感觉神经元。我们的短期目标是在体内分析神经感觉细胞形成和存活的分子生物学，这些细胞产生耳朵最重要的细胞类型并将它们连接起来。我们的长期目标是利用这些信息进行神经感觉再生，并引导生长的传入神经到达再生的毛细胞或刺激人工耳蜗的电极。在此应用中，我们将重点关注发育和连接毛细胞和感觉神经元所需的三个步骤。它们是神经感觉命运决定、神经感觉命运获得和神经感觉连接形成。所有这些事件都受到生长中的耳囊中表达的一系列基因的影响。我们将集中研究三个基因的作用及其可能的相互作用，使用复合突变小鼠确定耳朵的神经感觉区域，这些突变小鼠对于三个基因的各种组合（Aim1）无效或杂合。我们将继续研究三种主要 bHLH 基因在无效或杂合或新产生的转基因系中的各种组合中的作用，以剖析毛细胞和感觉神经元命运获得的分子机制（Aim2）。 Aim3 将通过使用转基因错误表达和靶向消除耳中的神经营养蛋白，将我们的研究扩展到新生儿和出生后小鼠，以了解神经营养蛋白对神经元纤维引导的作用。 AIM 1 将详细说明 FgflO、Gata3 和 Foxgl 在耳朵神经感觉发育中的作用。已知这三个因素在小鼠和果蝇的中枢和周围神经系统的神经感觉发育中相互作用，但它们在耳朵中的相互作用尚不清楚。 AIM 2 将测试 bHLH 基因（Atohl、Neurogl、Neurodl）在毛细胞和感觉神经元发育中的分子相互作用。识别可被操纵以产生所有神经感觉细胞的多能前体细胞可以极大地有益于当前恢复神经感觉听力损失的尝试。 AIM 3 将使用条件 Bdnf 耳突变结合转基因错误表达基因，从分子角度剖析神经营养素在新生儿和出生后纤维重组中的作用。这些信息对于控制神经营养因子在成人神经支配的再生、可塑性和维持方面的使用至关重要。