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）：我们的研究目标是了解发育中的内耳中控制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，因其组成细胞的复杂三维排列而引人注目，这些细胞包括神经元、感觉受体和组成小管、导管和其他特殊组织的非感觉细胞。形成这种结构所需的形态遗传机制很可能是脊椎动物共有的。在人类和动物模型中，由于先天性异常或疾病导致内耳精确形态的破坏可导致耳聋和/或平衡和平衡困难。我们努力了解导致内耳异常的基本缺陷，主要集中在正常发育过程和由于特定遗传缺陷而可能出现的一系列事件上。