Development studies of the inner ear

内耳发育研究

• 批准号: 7009897
• 负责人: Donna M Fekete
• 金额: $ 42.24万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009897
• 关键词: biological signal transduction; cadherins; cellular polarity; chick embryo; developmental genetics; developmental neurobiology; ear hair cell; electroporation; ganglion cell; in situ hybridization; laboratory mouse; labyrinth; otocyst /otolith; protooncogene; stem cells; transfection /expression vector; vertebrate embryology

DESCRIPTION (provided by applicant): The goal of our research is to understand the timing and molecular mechanisms that control patterning and cell fate specification in the developing inner ear. The inner ear, unique to vertebrates, is remarkable for the complex three-dimensional arrangement of its constituent cells, which include neurons, sensory receptors and non-sensory cells organized into tubules, ducts and other specialized tissues. It is likely that the morph genetic mechanisms required to form such structures will be shared by vertebrates. In humans and animal models, disruption of the precise morphology of the inner ear due to congenital anomalies or disease can result in deafness and/or to difficulties with balance and equilibrium. Our efforts to understand the fundamental defects that result in inner ear abnormalities are focused on both the normal processes of development and on the cascade of events that can arise as a result of a specific genetic defect. In this study, we aim to: (1) undertake lineage analysis of the progenitor cells in the ready chicken otocyst to reveal when distinct cell lineages diverge, such as sensory vs. non-sensory or neurogenic vs. nonneurogenic; (2) undertake lineage analysis in the mouse inner ear to determine whether hair cells and supporting cells share a common progenitor and whether there are cell lineage (compartment) boundaries in the organ of Corti; and (3) explore the role of the Wnt signaling pathway in cell fate specification in the ear, particularly with respect to the auditory vs. vestibular cell fate decision. Our studies will employ replication defective retroviral vectors to limit gene transfer to a small number of otic cells and their progeny. To study the Wnts, we will use replication-competent viruses to generate widespread misimpression for both gain-offunction and loss-of-function experiments. Together, the proposed studies should provide insight on the divergence of inner ear lineages. Our studies are designed to test a model of inner ear patterning that is based on the establishment of compartments and boundaries within the otic epithelium. Our data to date reveal that the auditory-vestibular fate decision can be manipulated through Wnt/b-catenin signaling. These findings, and new data generated from this study, may provide baseline data for a therapeutic strategy to direct stem cells along different developmental fates according to which sensory organ cell types may need to be replaced.

描述（由申请人提供）：我们研究的目的是了解控制内耳内耳的模式和细胞命运规范的时间和分子机制。脊椎动物独有的内耳对于其组成细胞的复杂三维排列而言是显着的，其中包括神经元，感觉受体和非感官细胞，这些细胞组织成小管，导管和其他专业组织。形成这种结构所需的形态遗传机制可能会由脊椎动物共享。在人类和动物模型中，由于先天性异常或疾病而导致内耳的精确形态的破坏会导致耳聋和/或困扰平衡和平衡。我们为理解导致内耳异常的基本缺陷的努力集中在正常的发展过程和由于特定遗传缺陷而可能引起的事件的级联。 在这项研究中，我们的目的是：（1）对现成的鸡耳囊中的祖细胞进行谱系分析，以揭示何时不同的细胞谱系分歧，例如感觉与非敏感或神经源性与非神经源性相比； （2）在小鼠内耳内进行谱系分析，以确定毛细胞和支撑细胞是否共有共同的祖细胞以及Corti器官中是否存在细胞谱系（室）边界； （3）探讨Wnt信号通路在耳朵中细胞命运规范中的作用，特别是在听觉与前庭细胞命运决策方面。我们的研究将采用复制有缺陷的逆转录病毒载体，以限制基因转移到少量的耳细胞及其后代。为了研究WNT，我们将使用竞争能力的病毒来产生广泛的误解，以实现增益后的功能和功能丧失实验。 拟议的研究共同提供了对内耳谱系差异的见解。我们的研究旨在测试基于在耳上皮内的隔室和边界的内耳模式模型。迄今为止，我们的数据表明，可以通过Wnt/B-catenin信号来操纵听觉 - 视野命运决策。这些发现以及本研究产生的新数据可能会为治疗策略提供基线数据，以根据需要更换感觉器官细胞类型来导致干细胞沿着不同的发育命运。