CELL CYCLE IN DEVELOPMENT / REGENERATION OF THE INNER EA

描述：(改编自《调查者摘要》)大多数听力损失和 平衡障碍是由于位于脑部的感觉毛细胞死亡 内耳的听觉和前庭系统。在低等脊椎动物中 细胞能够在受损后再生，但在哺乳动物中，这种能力是 要么缺席，要么极其有限。再生，就像胚胎发育， 需要控制细胞的生化机制之间的协调 与控制细胞分化和形态发生的细胞增殖 像内耳的感觉上皮一样的结构。长期的 这项建议的目的是了解信号转导途径 协调这一协调。这些路径很可能是 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的激酶 在调节细胞增殖过程中发挥重要作用的抑制物 发育，是建立正常细胞数量和 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的。突变的小鼠是 严重失聪。细胞的异常增殖在出生后仍在器官中持续。 与p27kip1在维持正常静止状态中的作用一致 状态，并阻碍损坏后的再生。 这项提议的目标是检验p27kip1调节细胞的假设。 内耳发育过程中Corti形态发生的数量和器官， 并探讨p27kip1在体内的调控机制。这一假设 将通过关联p27kip1在基因敲除和转基因小鼠中进行测试 随着细胞分裂的停止和随着 我们基因操作的形态后果(目标1)。接下来，我们将 研究p27kip1在发育过程中的表达受限模式 P27kip1基因和蛋白表达的时空相关性 在胚胎发育过程中的水平，随后通过使用转基因小鼠来测试 这些调控机制对Corti器官发育的意义 (目标2)。最后，我们将研究p27kip1在再生中的作用。 用p27kip1基因敲除小鼠比较再生反应 突变型和野生型动物之间。此外，我们还将比较 P27kip1在小鼠和鸡体内的表达调控 在毛细胞丢失后进行增殖增殖(目标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).