CELL CYCLE IN DEVELOPMENT / REGENERATION OF THE INNER EA

内脑区发育/再生中的细胞周期

• 批准号: 6379505
• 负责人: Neil Segil
• 金额: $ 26.33万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6379505
• 关键词: biological signal transduction; cell differentiation; cell growth regulation; chickens; cyclin dependent kinase; developmental genetics; developmental neurobiology; ear hair cell; enzyme inhibitors; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; nervous system regeneration; organ of Corti; transfection

DESCRIPTION: (Adapted from the Investigator's Abstract) Most hearing loss and balance disorders are due to the death of sensory hair cells located in the auditory and vestibular systems of the inner ear. In lower vertebrates these cells are able to regenerate following damage, but in mammals this capacity is either absent or extremely limited. Regeneration, like embryonic development, requires coordination between the biochemical machinery that governs cell proliferation with that which governs cell differentiation and morphogenesis of structures like the sensory epithelium of the inner ear. The long-term objective of this proposal is to understand the signal transduction pathways mediating this coordination. These pathways are likely to be good targets for future efforts to manipulate the process of regeneration. This laboratory has recently discovered that p27kip1, a cyclin-dependent kinase inhibitor that plays an important role in regulating cell proliferation during development, is a key element in establishing normal cell numbers and morphology of the organ of Corti. In mutant mice lacking the gene for p27kip1 the sensory hair cells and supporting cells are over-produced during embryogenesis bringing about morphological abnormalities. The mutant mice are severely deaf. Abnormal cell proliferation continues postnatally in the organ of Corti, consist with a role for p27kip1 in maintaining the normally quiescent state and impeding regeneration following damage. The goal of this proposal is to test the hypothesis that p27kip1 regulates cell number and organ of Corti morphogenesis during development of the inner ear, and to investigate the mechanism of p27kip1 regulation in vivo. This hypothesis will be tested in knockout and transgenic mice, by correlating p27kip1 developmental expression with the cessation of cell division and with the morphological consequences of our genetic manipulations (Aim 1). Next, we will study the restricted pattern of p27kip1 expression during development, first by correlating temporal and spatial expression of the p27kip1 mRNA and protein levels during embryogenesis and, subsequently, by using transgenic mice to test the significance of these regulatory mechanisms for organ of Corti development (Aim 2). Finally, the role of p27kip1 in regeneration will be investigated, using the p27kip1 knockout mice for a comparison of regenerative responses between mutant and wild type animals. In addition, we will compare the regulation of p27kip1 expression in mice and in chickens, which are able to undergo proliferative proliferation in response to hair cell loss (Aim 3).

描述：（根据调查人员的摘要改编）大多数听力损失和 平衡障碍是由于位于 内耳的听觉和前庭系统。在下脊椎动物中 细胞能够在伤害后再生，但是在哺乳动物中，这种能力是 缺乏或极为有限。像胚胎发展一样再生， 需要控制细胞的生化机械之间的协调 与控制细胞分化和形态发生的增殖 诸如内耳的感觉上皮之类的结构。长期 该建议的目的是了解信号转导途径 调解这种协调。这些途径可能是 未来操纵再生过程的努力。 该实验室最近发现P27KIP1是一种依赖细胞周期蛋白的激酶 在调节细胞增殖中起重要作用的抑制剂 开发，是建立正常单元格和的关键要素 Corti器官的形态。在缺乏p27kip1基因的突变小鼠中 感觉毛细胞和支持细胞在 胚胎发生导致形态异常。突变小鼠是 严重聋。异常细胞增殖在器官中持续 Corti的of Corti，与P27KIP1的作用一起维持正常静止 损坏后的状态和阻碍再生。 该提案的目的是检验p27KIP1调节细胞的假设 内耳发育过程中皮层形态发生的数量和器官， 并研究体内P27KIP1调节的机制。这个假设 通过将P27KIP1相关联在敲除和转基因小鼠中测试 通过停止细胞分裂以及与 我们的遗传操作的形态学后果（AIM 1）。接下来，我们会的 研究开发过程中p27KIP1表达的限制模式，首先 将p27KIP1 mRNA和蛋白质的时间和空间表达相关联 胚胎发生过程中的水平，随后使用转基因小鼠测试 这些调节机制对Corti发育器官的重要性 （目标2）。最后，将研究p27kip1在再生中的作用， 使用p27KIP1敲除小鼠进行再生反应的比较 在突变和野生型动物之间。另外，我们将比较 调节小鼠和鸡肉中P27KIP1的表达 响应毛细胞损失会发生增殖（AIM 3）。