YAP/TAZ in Schwann Cells as potential therapeutic targets in CMT1A and HNPP.
YAP/TAZ in Schwann Cells as potential therapeutic targets in CMT1A and HNPP.
批准号:
10537511
负责人:
Seth Michael Moore
金额:
$3.23万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-01 至 2026-07-31
关键词:
AblationAgeAllelesAnimalsBiochemicalBiopsyBiopsy SpecimenCell CycleCell Differentiation processCell NucleusCell ProliferationCellsCellular biologyCharcot-Marie-Tooth DiseaseClinicClinicalCommunicationComplexCritical ThinkingCryoultramicrotomyDefectDemyelinationsDevelopmentDiseaseEGR2 geneElasticityElectronsElectrophysiology (science)EmbryoEnvironmentGTP-Binding ProteinsGenesGeneticGenetic TranscriptionGlutaminaseGoalsHereditary neuropathy with liability to pressure palsiesHospitalsHumanImmunohistochemistryInheritedInstitutesIntegrinsIowaItalyKnock-outLaminin ReceptorLipidsMechanicsMediatingMicroscopicModelingMorphologyMusMyelinNerveNerve FibersNeurogliaNeuropathyNuclearPMP22 genePathologicPathologyPathway interactionsPatientsPeripheralPeripheral NervesPeripheral Nervous System DiseasesPermeabilityPhenotypePhosphorylationPhosphorylation InhibitionPhosphotransferasesPhysiciansPhysiologyPrevalenceProblem SolvingProteinsRadialRegulationResearchResistanceRoleSamplingSchwann CellsScientistSensorySignal PathwaySkinSorting - Cell MovementSourceTamoxifenTechniquesTestingTherapeuticTimeTrainingTranscription CoactivatorTranscriptional Coactivator with PDZ-Binding MotifTranscriptional RegulationTumor Suppressor ProteinsUniversitiesWestern Blottingbasebehavioral phenotypingcareerconditional knockoutcongenicdisease phenotypedosageexperienceexperimental studyimprovedmRNA Expressionmechanical propertiesmechanical signalmechanical stimulusmouse modelmyelinationneurophysiologynovelnovel therapeuticsoverexpressionranpirnasereceptorresponsesciatic nerveskillsskills trainingsural nervetherapeutic targettranscription factor
中文摘要
项目概要
一组异质性遗传性周围神经病被称为腓骨肌萎缩症,
估计患病率为 1:25001。在这些疾病中,腓骨肌萎缩症 1A (CMT1A) 和遗传性
伴有压力性麻痹的神经病 (HNPP) 是最常见的1。这些疾病源于
外周髓鞘蛋白 22 (PMP22)2 编码基因的重复 (CMT1A) 或缺失 (HNPP),导致
分别与其在雪旺细胞 (SC) 中的过度表达或表达不足相关3,4。这些使人衰弱的疾病无法治愈
疾病,强调需要确定调节 PMP22 表达的新机制,并阐明
周围神经(PN)脱髓鞘的病理机制。最近,由
具有 PDZ 结合基序 (TAZ)5 和转录因子 TEA 结构域 1 的转录共激活因子
(TEAD1)6,7,显示出正向调节 PMP22 表达8,9。因此,TAZ 激活的调节是
一种有趣的治疗途径,可以减少 CMT1A 中的 PMP22 转录,或增加其在 CMT1A 中的转录
HNPP。此外,PMP22 在 SC 生物学中的功能包括细胞周期调节10,11、细胞形成
连接和髓磷脂渗透性 12,13,并确定有髓 PN 纤维的机械性能 14,15。
值得注意的是,SC 生物学的这些方面也受到 TAZ 和相关转录共激活因子的调节
相关蛋白 1 (YAP)16–20; HIPPO 通路的主要下游效应器21,22。激活 YAP/TAZ
易位至细胞核并与 TEAD1-423,24 结合,改变许多必需基因的转录
用于 SC 增殖和分化,包括层粘连蛋白受体、整合素、G 蛋白 Ga、EGR2 和髓磷脂
和脂质基因8,20,25,26。因此,CMT1A和HNPP中YAP/TAZ激活状态的变化可能会影响
SC 的生理学,导致脱髓鞘。因此,我们假设修改 TAZ 表达可能
通过直接调节 PMP22 恢复适当的 PMP22 表达并改善 CMT1A 表型。
我们还假设 CMT1A 和 CMT1A 的小鼠模型和人类样本中的 YAP/TAZ 激活可能发生改变
HNPP,可能会改变 SC 增殖、髓磷脂渗透性和 PN 的机械性能。
为了确定调节 TAZ 激活的效果,PMP22-SC 中 TAZ 等位基因的基因消除
将评估过度表达小鼠的形态学、电生理学、感觉和行为学
表型拯救。 YAP/TAZ 激活改变的存在将通过免疫染色和
对人体活检样本以及 CMT1A 和 HNPP 小鼠模型进行生化分析。为此进行的研究
拟议的项目将在髓磷脂和神经胶质探索研究所进行,该研究所由
致力于研究髓磷脂及其相关疾病的跨学科科学家小组。整体
培训计划将强调科学沟通技巧的发展、各种技术的培训、
提高批判性思维和解决问题的能力,以及获得定期临床经验的机会。
这将为培养医师科学家职业所需的技能创造理想的环境。
英文摘要
Project Summary
The heterogeneous group of inherited peripheral neuropathies referred to as Charcot-Marie Tooth disease, have
an estimated prevalence of 1:25001. Among these disorders, Charcot Marie Tooth 1A (CMT1A) and Hereditary
Neuropathy with Liability to Pressure Palsy (HNPP) are the most common1. These diseases result from
duplication (CMT1A) or deletion (HNPP) of the gene encoding for peripheral myelin protein 22 (PMP22)2, leading
to its over or underexpression in Schwann cells (SCs), respectively3,4. There are no cures for these debilitating
diseases, highlighting the need to identify novel mechanisms to modulate PMP22 expression, and to elucidate
the pathological mechanisms involved in peripheral nerve (PN) demyelination. Recently, the complex formed by
the transcriptional coactivator with PDZ-binding motif (TAZ)5 and the transcription factor TEA domain 1
(TEAD1)6,7, was shown to positively regulate PMP22 expression8,9. Therefore, modulation of TAZ activation is
an intriguing therapeutic avenue to decrease PMP22 transcription in CMT1A, or increase its transcription in
HNPP. Moreover, the functions of PMP22 in SC biology include cell cycle regulation10,11, formation of cellular
junctions and myelin permeability12,13, and determining the mechanical properties of myelinated PN fibers14,15.
Notably, these aspects of SC biology are also regulated by TAZ, and the related transcriptional coactivator Yes-
associated protein 1 (YAP)16–20; the major downstream effectors of the HIPPO pathway21,22. Activated YAP/TAZ
translocate to the nucleus and associate with TEAD1-423,24, altering the transcription of many genes essential
for SC proliferation and differentiation including laminin receptors, integrins, G-protein Ga, EGR2, and myelin
and lipid genes8,20,25,26. Therefore, changes in the activation status of YAP/TAZ in CMT1A and HNPP may impact
the physiology of SCs, contributing to demyelination. Thus, we hypothesize that modifying TAZ expression may
restore proper PMP22 expression and ameliorate the phenotypes of CMT1A through direct regulation of PMP22.
We also postulate that YAP/TAZ activation may be altered in mouse models and human samples of CMT1A and
HNPP, potentially contributing to altered SC proliferation, myelin permeability, and mechanical properties of PNs.
To determine the effects of modulating TAZ activation, genetic ablation of TAZ alleles in SCs of PMP22-
overexpressing mice will be assessed for morphological, electrophysiological, sensory, and behavioral
phenotypic rescue. The presence of altered YAP/TAZ activation will be assessed through immunostaining and
biochemical analyses of human biopsy samples and mouse models of CMT1A and HNPP. The research for this
proposed project will be conducted at the Institute for Myelin and Glia Exploration, composed of an
interdisciplinary group of scientists dedicated to the study of myelin and its associated diseases. The overall
training plan will emphasize the development of scientific communication skills, training in various techniques,
improving critical thinking and problem-solving skills, as well as opportunities for regular clinical experiences.
This will create the ideal environment for developing the skills necessary for a career as a physician-scientist.
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会议论文
YAP/TAZ in Schwann Cells as Potential Therapeutic Targets in CMT1A and HNPP.
-
批准号:10730544
-
项目类别:
-
资助金额:$3.33万
-
财政年份:2022
-
负责人:Seth Michael Moore
-
依托单位:
国内基金
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