DEVELOPMENT STUDIES OF THE INNER EAR

内耳的发育研究

• 批准号: 6523434
• 负责人: Donna M Fekete
• 金额: $ 25.56万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523434
• 关键词: Retroviridae; Vesiculovirus; chick embryo; confocal scanning microscopy; congenital deafness; cyanine; developmental neurobiology; ear hair cell; epithelium; fluorescence microscopy; gene expression; gene mutation; genetic markers; histogenesis; laboratory mouse; otocyst /otolith; transfection /expression vector; vertebrate embryology

DESCRIPTION: (Adapted from the Investigator's Abstract) The goal of this research is to understand the molecular mechanisms that control patterning and cell fate determination 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 morphogenetic 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 anomalities or disease can result in deafness, and/or difficulties with balance and equilibrium, often accompanied by profound vertigo and nausea. The PI's 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 gene defect. The aims are to: (1) undertake a lineage analysis of the progenitor cells in the early chick otocyst to reveal when distinct cell lineages diverge, such as neurogenic vs. non-neurogenic or sensory vs. non-sensory; (2) undertake a lineage analysis of the mouse organ of Corti to determine whether hair cells and supporting cells share a common progenitor; (3) generate a fate map the chick otic cup to understand the relationships between gene expression and morphogenetic movements; and (4) force both focal and global perturbations of gene expression domains to help define the rules governing pattern formation in the eveloping inner ear. The studies will employ focal dye injections as well as infection with pseudotyped replication-defective retroviral vectors to limit gene transfer to a small number of otic cells and their progeny. The fourth aim will use replication-competent viruses to generate widespread misexpression of patterning genes. Together, the proposed studies should provide insight on the divergence of inner ear lineages and what role, if any, morphogenic movements and patterning genes play in the process. Their studies are designed to test a model of inner ear patterning that is based on the establishment of compartments and boundaries. The information provided by these animal studies may aid in understanding the molecular-genetic basis of human birth defects that cause deafness and vestibular dysfunction in humans.

描述：（根据调查员的摘要进行了改编） 研究是了解控制模式和 细胞命运在发展中的内耳中。内耳，独有的 脊椎动物对于它的复杂的三维布置是显着的 组成细胞，包括神经元，感觉受体和非感官 细胞组织成小管，管道和其他专用组织。很可能 形成这种结构所需的形态发生机制将是 由脊椎动物共享。在人类和动物模型中，精确的破坏 由于先天性异常或疾病而引起的内耳形态可能会导致 在耳聋和/或平衡和平衡方面的困难，通常 伴随着深刻的眩晕和恶心。 PI了解 导致内耳异常的基本缺陷都集中在这两个上 发展的正常过程以及可能出现的事件级联 由于特定的基因缺陷。 目的是：（1）对祖细胞中的祖细胞进行谱系分析 早期的雏鸡耳囊可揭示何时不同的细胞谱系分歧，例如 神经源与非神经成生或感觉与非感官； （2）承担a Corti小鼠器官的谱系分析以确定毛细胞是否 并支撑细胞共享一个共同的祖细胞； （3）生成命运图 鸡蛋杯了解基因表达与 形态发生运动； （4）强迫焦点和全球扰动 基因表达域，以帮助定义控制模式形成规则 不断发挥的内耳。这些研究也将采用焦点染料注射 作为伪型复制缺陷逆转录病毒载体的感染，以限制 基因转移到少量的耳细胞及其后代。第四目标 将使用复制能力的病毒来产生广泛的Misexpression 图案基因。 拟议的研究共同提供有关差异的见解 内耳谱系以及形态发生和图案的角色（如果有的话） 基因在此过程中发挥作用。他们的研究旨在测试内部模型 基于隔间的建立和 边界。这些动物研究提供的信息可能有助于 了解引起人类出生缺陷的分子遗传基础 人类的耳聋和前庭功能障碍。