CELL CYCLE IN DEVELOPMENT / REGENERATION OF THE INNER EA

描述：（改编自研究者摘要）大多数听力损失和 平衡失调是由于位于大脑中的感觉毛细胞死亡， 内耳的听觉和前庭系统。在低等脊椎动物中， 细胞能够在损伤后再生，但在哺乳动物中， 要么不存在，要么极其有限。再生，就像胚胎发育， 需要协调控制细胞的生化机制 增殖与控制细胞分化和形态发生的 像内耳的感觉上皮一样的结构。长期 这个建议的目的是了解信号转导途径 协调这种协调。这些途径可能是很好的靶点， 未来操纵再生过程的努力。 本实验室最近发现，p27kip1，一种细胞周期蛋白依赖性激酶， 抑制剂在调节细胞增殖过程中起重要作用， 发育，是建立正常细胞数量的关键因素， 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 导致形态异常的胚胎发生。突变小鼠是 严重失聪异常细胞增殖在出生后继续在器官 与p27kip1在维持正常静止的 状态和阻碍再生后的损害。 本研究的目的是验证p27kip1调控细胞凋亡的假说。 内耳发育过程中Corti形态发生的数量和器官， 探讨p27 kip1在体内的调控机制。这一假设 将在基因敲除小鼠和转基因小鼠中进行测试， 随着细胞分裂的停止， 我们的遗传操作的形态后果（目的1）。接下来我们就 研究发育过程中p27kip1表达的限制模式，首先通过 p27kip1 mRNA和蛋白表达的时空相关性 水平，并随后通过使用转基因小鼠进行测试， 这些调节机制对Corti器官发育重要性 (Aim 2）。最后，将研究p27kip1在再生中的作用， 使用p27kip1敲除小鼠比较再生反应 突变动物和野生动物之间的区别此外，我们将比较 调节小鼠和鸡中p27 kip1的表达， 响应于毛细胞损失而经历增殖性增殖（Aim 3）。

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).