Control of CNS Myelination by the E3 Ligase Component Fbxw7
E3 连接酶成分 Fbxw7 对 CNS 髓鞘形成的控制
基本信息
- 批准号:10388037
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAppointmentAxonBiological ModelsCell LineageCell ProliferationCellsComplexCullin ProteinsDemyelinating DiseasesDevelopmentDiseaseDorsalFBXW7 geneGeneticGenetic ModelsGenetic ScreeningGrowthHealthHomeostasisIndividualInstitutesKnock-outLaboratoriesLengthLifeLigaseMaintenanceMammalsMembraneMethodsModelingMolecularMorphologyMultiple SclerosisMusMutant Strains MiceMyelinMyelin Basic ProteinsMyelin SheathNeuraxisNeurogliaNeurologic SymptomsNeurosciences ResearchOligodendrogliaOptic NervePopulationProcessProtein IsoformsProteinsProteomicsRNA SplicingRegulationRodentRodent ModelRoleScienceSpeedSpinal CordThickTimeTrainingUbiquitinUbiquitinationZebrafishcareercell typedensityinnovationleukodystrophyloss of functionmouse geneticsmouse modelmutantmyelinationnew therapeutic targetnoveloligodendrocyte lineageoligodendrocyte precursorprecursor cellprotein Bprotein degradationprotein expressionremyelinationresponse to injuryskillstranscription factorubiquitin ligaseubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Myelination in the vertebrate central nervous system (CNS) is an evolutionarily conserved process where
oligodendrocytes (OLs), a glial cell type within the CNS, wrap surrounding axons in membrane sheaths providing
vital trophic support and insulation. This incredibly complex and dynamic process of myelination occurs
throughout life, both in response to injury and as a continuous refinement of circuit dynamics. A previous forward
genetic screen in zebrafish, aimed at identifying novel regulators of myelination, identified Fbwx7 as a negative
regulator of CNS myelination. Fbxw7 is a recognition subunit of the SKP1-Cullin-Fbox (SCF) ubiquitin ligase
complex. Loss of Fbxw7 resulted in a significant increase in myelin basic protein (mbp) expression, the number
of OL lineage cells, and an increase in the number of myelinated axons and myelin wraps in the dorsal spinal
cord of zebrafish. Additionally, loss of Fbxw7 in mature myelinating OLs in the mouse optic nerve resulted in a
significant increase in the density of abnormally thick myelinated axons, myelin outfoldings, and degenerating
axons, showing for the first time a role for Fbxw7 in regulating myelin homeostasis in the mammalian CNS. To
determine the substrates that Fbxw7 might be regulating to control CNS myelination, I silenced Fbxw7 in primary
OL cultures, and found a significant increase in the levels of the transcription factor Myelin Regulator Factor
(Myrf), a key protein essential for myelination, and many novel proteins. I hypothesize that Fbxw7 controls CNS
myelination by degrading protein substrates that regulate OPC proliferation, differentiation, and/or OL sheath
length and myelin thickness. To investigate this, I will 1) examine OL development and dynamics in Fbxw7 loss
of function zebrafish mutants and in OL lineage specific Cre mouse models, and 2) determine Fbxw7 substrates
that regulate OL development and myelination using zebrafish genetics and rodent culture models. By combining
these approaches, I will receive training in a diverse array of experimental methods and model systems, providing
me with skills and options to pursue a successful career in science. Additionally, my co-appointment in Dr. Ben
Emery’s (Jungers Center for Neuroscience Research) and Dr. Kelly Monk’s (Vollum institute) laboratories will
provide me with institutional support from two exemplary departments and access to a large group of diverse
PIs and trainees to aid in my scientific growth and training.
项目摘要
脊椎动物中枢神经系统(CNS)中的mylination是一个进化保守的过程
少突胶质细胞(OLS),CNS中的神经胶质细胞类型,膜覆盖物周围的轴突覆盖了膜覆盖物
重要的营养支撑和绝缘。
在一生中,无论是响应伤害还是作为电路动力学的连续完善。
斑马鱼中的遗传屏幕,旨在识别髓鞘形成的新型调节剂,将FBWX7识别为ASA负面
CNS髓鞘的调节器。
复合物的损失。
OL谱系细胞的数量,并增加背脊柱中的髓鞘轴突和髓磷脂。
斑马鱼的绳索。
异常厚的髓鞘轴突,髓磷脂外褶和退化的密度显着增加
轴突首次显示FBXW7在调节哺乳动物CNS中的髓鞘稳态中的作用
确定FBXW7可能正在调节以控制CNS髓鞘的底物,我将FBXW7沉默
OL培养物,发现转录因子髓磷脂调节因子的水平显着增加
(MYRF),一种关键蛋白质,对髓鞘形成必不可少,许多新型蛋白质。
通过降解调节OPC透音,差异和/或OL修剪的蛋白质底物的髓鞘形成。
长度和髓磷脂厚度。
功能斑马鱼突变体和OL谱系特定的CRE小鼠模型,以及2)确定FBXW7底物
使用斑马鱼遗传学和啮齿动物培养模型来调节OL发育和髓鞘
这些方法,我将接受各种实验方法和模型系统的培训,提供
我的技能和选择是在科学领域成功的职业。
埃默里(Emery)(神经科学研究的荣格)和凯利·蒙克(Vollum Institute)实验室Willl
为我提供来自两个示例部门的研究所的支持,并获得了一大批不同
PI和培训以帮助我的科学成长和培训。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hannah Young Collins的其他文献
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{{ truncateString('Hannah Young Collins', 18)}}的其他基金
Control of CNS Myelination by the E3 Ligase Component Fbxw7
E3 连接酶成分 Fbxw7 对 CNS 髓鞘形成的控制
- 批准号:
10552572 - 财政年份:2021
- 资助金额:
$ 4.68万 - 项目类别:
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