p27(Kip1) and Retinal Attachment
p27(Kip1) 和视网膜附着
基本信息
- 批准号:7366889
- 负责人:
- 金额:$ 21.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-12-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:AblationActinsAddressAdhesionsAdultAnimalsApicalAreaBinding SitesBiologicalBiological AssayBreedingCDKN1B geneCell CycleCell Cycle ProteinsCell Cycle RegulationCell NucleusCell ProliferationCell physiologyCellsComplexCyclin D1Cyclin-Dependent KinasesCyclinsCytoplasmCytoskeletonDNADataDefectDevelopmentDisruptionDysplasiaElectronsEngineeringEpithelialEpithelial CellsEpitheliumEventExcisionExhibitsGene TargetingGenerationsGenesGeneticGoalsHandKnock-in MouseKnockout MiceLightMaintenanceMethodsMicroscopicMolecularMouse StrainsMusMutant Strains MiceMutationNeural RetinaNuclearNuclear ExportPhenotypePhosphorylationPhosphorylation SitePhotoreceptorsPlayPoint MutationProcessPropertyProtein Export PathwayProteinsRegulator GenesResearchRetinalRetinal DetachmentRetinal DysplasiaRoleSignal TransductionSiteStructure of retinal pigment epitheliumSystemTestingTissuesTyrosinase related protein-1VisionWestern Blottingbasebcl-1 Genescellular microvilluscyclin-dependent kinase inhibitor 1Bdensitygastrointestinal microvillushuman TYRP1 proteininhibitor/antagonistmutantp27 Cell Cycle Proteinp27 Enzyme Inhibitorpromoterprotein expressionprotein functionrecombinaseresearch studyrho GTP-Binding Proteins
项目摘要
DESCRIPTION (provided by applicant): The proposed research has as its overall goal to define mechanisms that underlie normal retinal attachment, with the aim that better methods of restoring the interaction between the neural retina and its supporting retinal pigment epithelium (RPE) may be developed, and thus loss of visual function resulting from retinal detachment ameliorated. Little is known about how the structural components of the RPE-neural retina interface are generated, in terms of specific signaling events and their sequence of activation in development. The proposed experiments focus specifically on the role of the epithelium, and will make use of a strain of mice that is deficient in the cell cycle regulatory protein p27(Kip1). Aside from retinal proliferative defects and limited foci of retinal dysplasia, these animals exhibit broad areas of retinal detachment, evident as a loss of interdigitation between photoreceptor outer segments and RPE microvilli. Aim 1 will test the hypothesis that p27(Kip1) plays a role in establishment and maintenance of the RPE-neural retina interface that is independent of its involvement in epithelial cell cycle regulation. For these experiments, two strains of knock-in mice will be examined using established light and electron microscopic methods. The first strain (p27CK-) contains point mutations in the p27(Kip1) binding sites for cyclins and cyclin-dependent kinase (CDK), resulting in a protein that is unable to act as a cell cycle inhibitor, but nevertheless retains its cytoskeleton regulatory properties. In the second strain (p27S10A), the major phosphorylation site regulating p27(Kip1) protein export to the cytoplasm has been altered, yielding a protein that can carry out its function as a negative regulator of cell proliferation within the nucleus but is unable to influence the actin cytoskeleton. The possibility that the p27(S10A) mutation causes the induction of retinal detachment, and that p27CK- rescues detachment resulting from p27(Kip1) gene ablation will be examined. Finally, the possibility that retinal detachment is due to increased RPE cellular or nuclear density per se will be examined by crossing p27(Kip1)-null mice with mice lacking the positive cell cycle regulatory gene cyclin D1. Aim 2 will examine whether the retinal detachment we observe in p27(Kip1)-null mice results, at least in part, from a loss of protein function specifically within the epithelium. To test this, the Cre-lox system for conditional gene targeting will be implemented to ablate the p27(Kip1) gene selectively in RPE cells.
描述(由申请人提供):拟议的研究的总体目标是定义正常视网膜附着的机制,其目的是更好地恢复神经视网膜与其支撑性视网膜色素上皮(RPE)之间的相互作用的方法,从而可以得到视网膜脱离的损失。关于如何在特定的信号事件及其发育中激活序列的角度生成RPE神经视网膜界面的结构成分知之甚少。提出的实验专门针对上皮的作用,并将利用在细胞周期调节蛋白p27(KIP1)中缺乏小鼠的菌株(KIP1)。除了视网膜增殖缺陷和视网膜发育不良的焦点有限外,这些动物还表现出广泛的视网膜脱离区域,这显然是光感受器外部段和RPE微绒毛之间互插的丧失。 AIM 1将检验以下假设:P27(KIP1)在RPE神经视网膜界面的建立和维持中起作用,该界面与其参与上皮细胞周期调节无关。对于这些实验,将使用已建立的光和电子显微镜方法检查两种敲入小鼠。第一个菌株(p27CK-)包含细胞周期蛋白和细胞周期蛋白依赖性激酶(CDK)的p27(Kip1)结合位点中的点突变,导致蛋白质无法充当细胞周期抑制剂,但仍然保留其细胞骨骼调节性质。在第二株(P27S10A)中,已改变了调节p27(KIP1)蛋白导出到细胞质的主要磷酸化位点已改变,从而产生一种蛋白质,该蛋白可以作为细胞核内细胞增殖的负调节剂的功能,但无法影响肌动蛋白细胞骨骼。 P27(S10A)突变引起视网膜脱离的可能性,并将检查p27CK-救援p27(KIP1)基因消融产生的脱离。最后,视网膜脱离是由于RPE细胞或核密度增加所致的可能性,将通过将P27(KIP1)无小鼠与缺乏阳性细胞周期调节基因Cyclin d1的小鼠进行检查。 AIM 2将检查我们在p27(KIP1) - null小鼠中观察到的视网膜脱离,至少部分地是由于上皮内的蛋白质功能的丧失。为了测试这一点,将实现用于条件基因靶向的CRE-LOX系统,以在RPE细胞中选择性地消除P27(KIP1)基因。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Corneal endothelial cells possess an elaborate multipolar shape to maximize the basolateral to apical membrane area.
角膜内皮细胞具有复杂的多极形状,以最大化基底外侧至顶膜面积。
- DOI:
- 发表时间:2016
- 期刊:
- 影响因子:2.2
- 作者:Harrison,TheresaA;He,Zhiguo;Boggs,Kristin;Thuret,Gilles;Liu,Hong-Xiang;Defoe,DennisM
- 通讯作者:Defoe,DennisM
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Dennis Michael Defoe其他文献
Dennis Michael Defoe的其他文献
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{{ truncateString('Dennis Michael Defoe', 18)}}的其他基金
RETINAL ATTACHMENT AND OUTER SEGMENT TURNOVER IN VITRO
体外视网膜附着和外节翻转
- 批准号:
2161206 - 财政年份:1988
- 资助金额:
$ 21.3万 - 项目类别:
RETINAL ATTACHMENT AND OUTER SEGMENT TURNOVER IN VITRO
体外视网膜附着和外节翻转
- 批准号:
3263877 - 财政年份:1988
- 资助金额:
$ 21.3万 - 项目类别:
RETINAL ATTACHMENT AND OUTER SEGMENT TURNOVER IN VITRO
体外视网膜附着和外节翻转
- 批准号:
3263879 - 财政年份:1988
- 资助金额:
$ 21.3万 - 项目类别:
IMMUNOLOGIAL APPROACHES TO OUTER SEGMENT DISASSEMBLY
外节拆卸的免疫学方法
- 批准号:
3263880 - 财政年份:1988
- 资助金额:
$ 21.3万 - 项目类别:
RETINAL ATTACHMENT AND OUTER SEGMENT TURNOVER IN VITRO
体外视网膜附着和外节翻转
- 批准号:
2161205 - 财政年份:1988
- 资助金额:
$ 21.3万 - 项目类别:
IMMUNOLOGIAL APPROACHES TO OUTER SEGMENT DISASSEMBLY
外节拆卸的免疫学方法
- 批准号:
3263875 - 财政年份:1986
- 资助金额:
$ 21.3万 - 项目类别:
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