miR-34/449 miRNAs regulate ciliogenesis and cerebrospinal fluid production in choroid plexus
miR-34/449 miRNAs regulate ciliogenesis and cerebrospinal fluid production in choroid plexus
批准号:
9350418
负责人:
Lin He
金额:
$23.55万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2018-08-31
关键词:
ApicalBlood VesselsBlood capillariesBrainCellsCellular MorphologyCellular biologyCerebral VentriclesCerebrospinal FluidCiliaCodeComplexConnective TissueDefectDevelopmentDevelopmental ProcessElectron MicroscopyEmployee StrikesEpithelial CellsExcisionExhibitsFamilyGenesGeneticHistologyImage AnalysisImpairmentIn VitroLengthMaintenanceMediatingMetabolicMicroRNAsMicrotubulesMolecularMolecular BiologyMorphologyMusNeuraxisNutritionalOrgan Culture TechniquesOrganellesPathway interactionsPlayProductionProteinsRegulationRegulator GenesRoleStructure of choroid plexusSystemTissuesapical membranebasebrain volumecandidate validationcapillarycell motilitycell typecilium biogenesiscilium motilitygene repressionimpaired brain developmentinsightmonolayermouse modelwasting
中文摘要
项目总结
脉络丛是一种高度血管化的分泌组织,伸入大脑。
脑室,其主要功能是产生脑脊液(CSF)。证金公司提供
为大脑发育提供营养和新陈代谢支持,并促进有效的废物清除。
脉络丛由一层顶端单层纤毛上皮细胞围绕基质组成
毛细血管和结缔组织的核心。脉络丛上皮细胞(CPECs)各自形成
一到二十打纤毛,这是基于微管的细胞器,从顶端突出
薄膜。越来越多的证据表明纤毛在脉络丛中的重要性。
发育和功能,因为纤毛发生缺陷之间已经建立了联系
脉络丛和小鼠过量产生脑脊液。我们的初步研究发现,
高度冗余的miRNA家族miR-34/449miRNAs是CPEC纤毛发生的关键调控因子。
MiR-34/449家族包括6个进化上保守的同源miRNAs,它们是
在纤毛的CPEC中高度浓缩。MIR-34/449缺陷小鼠的特征是
脑室大小,CPEC形态异常和大脑发育受损,提示
由于脉络丛功能缺陷,脑脊液产量减少。有趣的是,最早的
我们可以在miR-34/449缺陷的脉络丛中检测到的缺陷是CPECs的异常纤毛生成,
以每细胞纤毛数量显著增加和纤毛长度较长为特征
轴丝。鉴于CPEC纤毛在负向调节脑脊液产生方面的功能重要性,
我们假设miR-34/449缺乏导致CPEC过度纤毛生成,从而
抑制脑脊液的产生,损害大脑发育。在这里,我们建议在功能上
鉴定miR-34/449miRNAs在CPEC纤毛发生和脑脊液产生中的作用,并阐明
潜在的细胞和分子机制。利用遗传小鼠模型,脉络丛在
体外培养,细胞生物学和分子生物学的方法,我们将表征细胞和
MiR-34/449-TKO脉络丛中的分子缺陷及其功能联系
CPEC纤毛与脉络丛功能之间的关系。我们还将确定MIR-34/449的主要目标
介导CPEC纤毛发生和脑脊液产生。我们的研究不仅将揭示一个高度的
中巴经济走廊纤毛发生的强有力的调控机制,但也提供了对
CPEC纤毛在脉络丛功能中的作用
英文摘要
Project summary
The choroid plexus is a highly vascularized, secretory tissue that protrudes into the brain
ventricles, whose primary function is to produce cerebrospinal fluid (CSF). CSF provides
nutritional and metabolic support for brain development and mediates efficient waste removal.
Choroid plexus consists of an apical monolayer of ciliated epithelial cells that surround a stromal
core of capillaries and connective tissues. Choroid plexus epithelial cells (CPECs) each forms
one to two dozen cilia, which are microtubule-based organelles that project from the apical
membrane. Emerging evidence has suggested the importance of cilia in choroid plexus
development and function, as a connection has been established between a defective ciliogenesis
in choroid plexus and the excessive CSF production in mice. Our preliminary studies identified a
highly redundant miRNA family, miR-34/449 miRNAs, as the key regulators for CPEC ciliogenesis.
The miR-34/449 family comprises six evolutionarily conserved, homologous miRNAs that are
highly enriched in the ciliated CPECs. miR-34/449-deficient mice are characterized by reduced
brain ventricle size, aberrant CPEC morphology and impaired brain development, suggesting a
reduced CSF production due to defective choroid plexus functions. Interestingly, the earliest
defect we can detect in miR-34/449-deficient choroid plexus is the aberrant ciliogenesis in CPECs,
characterized by a significant increase of the cilium number per cell and a greater length of the
axonemes. Given the functional importance of CPEC cilia in negatively regulating CSF production,
we hypothesize that the miR-34/449 deficiency leads to excessive CPEC ciliogenesis, which
represses CSF production and impairs brain development. Here, we propose to functionally
characterize miR-34/449 miRNAs in CPEC ciliogenesis and CSF production, and to elucidate the
underlying cellular and molecular mechanisms. Using genetic mouse models, choroid plexus in
vitro culture, cell biology and molecular biology approaches, we will characterize the cellular and
molecular defects in miR-34/449-TKO choroid plexus, and investigate the functional connection
between CPEC cilia and choroid plexus function. We will also identify the key miR-34/449 targets
that mediate CPEC ciliogenesis and CSF production. Our studies will not only reveal a highly
robust regulatory mechanism for CPEC ciliogenesis, but also provide important insights into the
functional importance of CPEC cilia in choroid plexus function.
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