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Cell cycle in development and regeneration of the inner ear

内耳发育和再生中的细胞周期

基本信息

批准号：
7738906
负责人：
Neil Segil
金额：
$ 38.72万
依托单位：
HOUSE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738906
关键词：
Address Adult Affect Age Birds Cell Count Cell Cycle Cell Cycle Regulation Cell Death Cell Differentiation process Cell Proliferation Cell division Cells Cochlea Cochlear duct Complex Corwin Cyclin-Dependent Kinase Inhibitor Data Defect Development Differentiation and Growth Down-Regulation Embryonic Development F-Box Proteins Failure Family Figs - dietary Genes Genetic Genetic Transcription Goals Grant Hair Cells In Vitro Investigation Labyrinth Maintenance Mammals Methods Molecular Morphogenesis Mus Mutant Strains Mice Natural regeneration Normal Cell Notch Signaling Pathway Organ Organ of Corti Pathway interactions Pattern Perinatal Play Point Mutation Post-Transcriptional Regulation Process Proliferating Proteins Proteolysis Publishing Regulation Relative (related person)Reporting Research Personnel Role Ruthenium Ben SKP Cullin F-Box Protein Ligases Sensory Hair Series Signal Transduction Supporting Cell Techniques Tertiary Protein Structure Therapeutic Intervention Time Transcriptional Regulation Ubiquitin Vertebrates Wild Type Mouse age related base deafness hair cell regeneration in vivo inhibitor/antagonist insight loss of function mutation mutant notch protein postnatal premature progenitor programs protein degradation regenerative response tool

项目摘要

Loss of sensory hair cells in mammals results in permanent deafness because regeneration does not occur. The loss of regenerative ability is tied to the inability of the specialized supporting cells within the organ of Corti to begin dividing in response to hair cell death. We have taken a developmental approach to this problem. Our hope is that by thoroughly understanding the process by which the cells of the organ of Corti stop dividing during embryogenesis, we will gain insight into why regeneration does not occur. In doing so, we hope to provide tools and targets for therapeutic intervention into the problem of deafness. During development of the organ of Corti, control of cell proliferation is tightly coordinated with the process of cell differentiation and patterning (Ruben, 1968). We have shown that the cyclin-dependent kinase inhibitor p27Klp1 is required for timing this coordination. In p27Klp1 mutant mice, cell cycle exit is delayed, leading to supernumerary cells, a disruption of the orderly pattern of hair cell organization, and deafness (Chen and Segil, 1999). Although p27Klp1 abundance is widely believed to be regulated at the post-transcriptional level through control of protein turnover, our results indicate that transcriptional regulation of p27Klp1 is largely, though not entirely, responsible for the determining the number of cells in the mature organ. Additional preliminary data indicates that Notch pathway signaling may be a key player in regulating p27 transcription during organ of Corti formation. In Specific Aim 1 we analyze the role of Notch signaling in the spatial and temporal regulation of p27Klp1 transcription during embryogenesis of the organ of Corti. In spite of the importance of p27Klp1 transcriptional regulation, we have observed that in Skp2 mutant mice, there is also a defect in cell cycle exit and organ of Corti structure. Skp2 is part of the SCF-ubiquitin ligase complex that is involved in regulating p27Klp1 protein turnover. In Specific Aim 2 we address the role of post-transcriptional mechanisms in the regulation of p27Klp1. Finally, in Specific Aims 3 and 4 we address the problem of regeneration directly, by studying p27Klp1 regulation in postnatal supporting cells. We have recently developed techniques that allow us to purify postnatal supporting cells and grow them in vitro. In doing so, we have discovered that perinatal supporting cells retain the capacity to reenterthe cell cycle and divide, while supporting cells from P14 mice are unable to do so. Changes in the ability of P14 supporting cells to down-regulate p27Kip1 are partly responsible for the block to cell division that results in the lack of regeneration. This specific aim investigates the molecular basis for the age-dependent change in p27 regulation that we hypothesize underlies the lack of regeneration in the mammalian innerear.

哺乳动物失去感觉毛细胞会导致永久性耳聋，因为不能再生