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）：耳朵的神经感觉成分提取前庭和听觉信息并将其传递到大脑的神经感受器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生存的分子生物学，并产生耳朵的最关键细胞类型并将其连接起来。我们的长期目标是将这些信息用于神经感觉再生，并指导成长的传入以达到再生毛细胞或刺激耳蜗植入物的电极。我们将重点放在开发和连接毛细胞和感觉神经元所需的三个步骤上。这些是神经感觉的命运确定，神经感觉的获取和神经感觉连接的形成。所有这些事件都受到在不断增长的耳囊中表达的基因级联的影响。我们将使用复合突变体小鼠的三个基因的作用及其可能的相互作用来确定耳朵的神经感觉区域，这些突变体小鼠对于三个基因的各种组合（AIM1）而言是无效或杂合的。我们将继续研究三个主要BHLH基因在零或杂合的各种组合中的作用，或者在新生成的转基因线中，以剖析毛细胞和感觉神经元命运的分子机制（AIM2）。 AIM3将通过使用转基因Misexpression和靶向消除耳朵中神经营养的神经元纤维引导的神经营养蛋白在神经元纤维引导中的作用扩展我们的研究。 AIM 1将指定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苍蝇的中央和周围神经系统中的神经感觉发育中相互作用，但是它们在耳朵中的相互作用尚未阐明。 AIM 2将测试毛细胞和感觉神经元发育中BHLH基因（Atohl，Neurogl，NeuroDL）的分子相互作用。识别可以操纵以产生所有神经感觉细胞的多能前体可以极大地有助于恢复神经感觉听力损失的尝试。 AIM 3将使用条件BDNF耳朵突变与转基因Misexpressor结合使用，将神经营养蛋白在新生儿和产后纤维重组中的作用分子剖析。这种信息对于控制神经营养蛋白的使用至关重要。