The role of the extracellular matrix in establishing Schwann cell polarity
细胞外基质在建立雪旺细胞极性中的作用
基本信息
- 批准号:10604797
- 负责人:
- 金额:$ 4.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcademiaAddressAdultAgeAscorbic AcidAxonBasal laminaBehavioral AssayBindingBinding SitesCaliberCell CommunicationCell Culture TechniquesCell MaintenanceCell MaturationCell PolarityCell physiologyCell secretionCellsClustered Regularly Interspaced Short Palindromic RepeatsCo-ImmunoprecipitationsCollagen ReceptorsCollagen Type IVComplexCuesCyclic AMP-Dependent Protein KinasesCytoskeletonDataDefectDemyelinating DiseasesDevelopmentDevelopmental Delay DisordersDoctor of PhilosophyEducational workshopElectron MicroscopyEnvironmentEpithelial CellsExonsExperimental DesignsExtracellular MatrixExtracellular SpaceExtracellular StructureG-Protein-Coupled ReceptorsGenesGoalsHealthImmunofluorescence ImmunologicIn VitroIntegrin alpha2IntegrinsKnock-outLaboratoriesLearningLoxP-flanked alleleManuscriptsMediatingMembraneMorphologyMotorMusMutationNeurogliaNeurosciencesPAWR genePerceptionPeripheral NervesPeripheral Nervous SystemPeripheral Nervous System DiseasesPhenocopyPhenotypePrimary Cell CulturesPrincipal InvestigatorProcessProtein BiochemistryProteinsPublishingResearchRoleSTK11 geneSchwann CellsSensorySignal TransductionSpecific qualifier valueTechniquesTestingTrainingViralWestern BlottingWorkWritingbasolateral membranecareercareer developmentcell typeexperimental studyin vivoinsightintercalationloss of functionmolecular sequence databasemutantmyelinationnovelpainful neuropathypolarized cellposterspreventprogramsreceptorrecruitsciatic nerveskill acquisitiontenure track
项目摘要
Abstract
Various cell types establish polarity to generate complex morphology and exert function. Schwann cells
(SCs) are polarized with an adaxonal membrane facing the axon and a basolateral membrane facing the
extracellular matrix (ECM). Previous work established that known polarity proteins, Par-3 and LKB-1/Par-4,
localize to the adaxonal membrane prior to myelination and are required within SCs for the timely progression of
myelination and Remak bundle formation. Although SC polarity is critical for proper peripheral nerve
development, the mechanism for establishing polarity within SCs remains unknown. The basal lamina, a
specialized structure of the ECM that abuts the basolateral membrane, is believed to be important for regulating
polarity; additionally, in other epithelial cells collagen-IV is necessary for the establishment of polarity. SCs
secrete collagen-IV into the basal lamina and express integrin alpha2, a collagen-IV receptor also known for its
role in polarity. Therefore, I hypothesize that collagen-IV initiates SC polarity by signaling through integrin alpha2
and is necessary for rSC polarity but dispensable for myelination. I test this possibility by analyzing the role of
SC secreted collagen-IV on peripheral nerve development, determining whether collagen-IV within the SC basal
lamina is necessary and sufficient for SC polarity, and identifying the SC binding partner for collagen-IV.
Preliminary data suggests that SC-secreted collagen-IV is important for timely myelination and Remak bundle
formation. These results phenocopy those observed when polarity is disrupted by knocking out LKB1 specifically
from SCs. Upon completion, this study will have important implications on the integration of extrinsic signals from
the ECM onto the internal cell state. Thereby regulating polarity, which is critical for peripheral nerve health.
Additionally, understanding the results and mechanisms of polarity defects can inform the understanding of
peripheral neuropathies. In order to perform these studies, I will learn various techniques including protein
biochemistry, including Western blot and co-immunoprecipitation, primary cell culture techniques, CRISPR-
based gene editing, mouse behavioral assays, and viral construction/purification/transduction under the
guidance of my sponsor Dr. Jonah Chan. I will receive additional training of career development skills such as
experimental design, presenting posters/presentations, manuscript writing, and manuscript reviewing through
my sponsor, classes within the UCSF Neuroscience Program, and workshops through UCSF Office of Career
and Professional Development. I am confident that the rigorous training I receive during my PhD at UCSF will
enable me to pursue my long-term goal of becoming a tenure track principal investigator within academia.
摘要
不同类型的细胞建立了极性,以产生复杂的形态和发挥功能。雪旺细胞
(SCS)被极化,轴突膜面向轴突,基底外侧膜面向轴突
细胞外基质(ECM)。先前的工作证实,已知的极性蛋白PAR-3和LKB-1/PAR-4,
在髓鞘形成前定位于轴突细胞膜,在干细胞内是及时进展所必需的
髓鞘形成和Remak束形成。尽管SC的极性对正常的周围神经至关重要
在发育过程中,在干细胞内建立极性的机制仍不清楚。基板,一种
靠近基底膜的细胞外基质的特殊结构被认为对调节
极性;此外,在其他上皮细胞中,IV型胶原是建立极性所必需的。SCS
分泌IV型胶原到基底膜并表达整合素α2,这是一种IV型胶原受体,也以其
在极性中扮演的角色。因此,我假设IV型胶原通过整合素α2信号启动SC的极性。
对于RSC的极性是必需的,但对于髓鞘形成是必不可少的。我通过分析这个角色来测试这种可能性
SC在周围神经发育过程中分泌IV型胶原,决定了在SC基础上是否存在IV型胶原
薄层是SC极性的必要条件和充分条件,并识别IV型胶原的SC结合伙伴。
初步数据表明,SC分泌的IV型胶原对及时的髓鞘形成和Remak束很重要
队形。这些结果与通过特异性敲除LKB1而破坏极性时观察到的结果相同
来自SCS。完成后,这项研究将对整合外部信号具有重要意义
将ECM转换到内部单元状态。从而调节极性,这对周围神经健康至关重要。
此外,了解极性缺陷的结果和机制可以帮助理解
周围神经病。为了进行这些研究,我将学习各种技术,包括蛋白质
生物化学,包括蛋白质印迹和免疫共沉淀,原代细胞培养技术,CRISPR-
基于基因编辑、小鼠行为分析和病毒构建/纯化/转导
我的赞助人陈可辛博士的指导。我将接受额外的职业发展技能培训,例如
实验设计,展示海报/演示,手稿写作,手稿审阅
我的赞助人,加州大学旧金山分校神经科学项目中的课程,以及通过加州大学旧金山分校职业办公室举办的研讨会
和专业发展。我相信,我在加州大学旧金山分校攻读博士期间接受的严格培训将会
使我能够追求我的长期目标,成为学术界的终身教职首席研究员。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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