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(申请人提供)：耳朵中提取前庭和听觉信息并将其传导到大脑的神经感觉组件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，这些细胞产生并连接耳朵最关键的细胞类型。我们的长期目标是将这些信息用于神经感觉再生，并引导生长中的传入细胞到达再生的毛细胞或耳蜗植入物的刺激电极。在这一应用中，我们将重点介绍发展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正在生长的耳囊中表达的一系列基因的影响。我们将利用对三个基因的不同组合(Aim1)无效或杂合的复合突变小鼠，集中讨论三个基因的作用及其可能的相互作用，这些基因决定了耳朵的神经感觉区域。我们将继续研究三个主要的bHLH基因在各种缺失或杂合性组合中的作用，以及在新产生的转基因系中的作用，以剖析毛细胞和感觉神经元命运获得(AIM2)的分子机制。AIM3将扩大我们对新生儿和出生后小鼠的研究，通过使用转基因错误表达和有针对性地消除耳朵中的神经营养因子，神经营养因子在神经纤维引导中的作用。目标1将明确FgflO、GATA3和Foxg1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枢和外周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。目的2研究毛细胞和感觉神经元发育过程中bHLH基因(Atoh1、Neurog1、Neurod1)的分子相互作用。识别出可以被操纵以产生所有神经感觉细胞的多潜能前体细胞，可能会极大地有利于目前恢复神经感觉听力损失的尝试。目的3利用条件性脑源性神经营养因子EAR突变结合转基因错误表达基因，从分子水平剖析神经营养因子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用于再生、可塑性和维持成人神经支配至关重要。