Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease
研究腓骨肌萎缩症的病理机制
基本信息
- 批准号:10541701
- 负责人:
- 金额:$ 3.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmino AcidsAmino Acyl-tRNA SynthetasesAntioxidantsAuditory systemAxonBinding SitesBiological AssayBrain StemCell LineCell NucleusCell physiologyCellsCharcot-Marie-Tooth DiseaseClinicalCochleaCytosolDNA DamageDefectDevelopmentDiseaseEducational process of instructingEducational workshopEnzymesEpithelialExhibitsFamilyFamily memberFibroblastsGene ExpressionGene FamilyGenesGenetic TranscriptionGoalsHSPB1 geneHereditary Motor and Sensory Neuropathy Type IHereditary Motor and Sensory-Neuropathy Type IIHindlimbHumanImageImpaired cognitionInheritedInvestigationLinkLongitudinal StudiesMapsMetabolismMidbrain structureMitochondriaModelingMolecularMolecular ProfilingMolecular TargetMorphologyMotorMotor NeuronsMusMutateMutationMyelin SheathNeurogliaNeurologic EffectNeuronsNeurosciencesNuclearNuclear Localization SignalOrganellesOrganismOxidative StressPMP22 genePathogenesisPathogenicityPathologyPathway interactionsPatientsPeripheral Nervous System DiseasesPersonsPhasePhenotypePhysiologicalPhysiologyPlayProductionPropertyProtein BiosynthesisProteinsResearchResearch Project GrantsRoleSchwann CellsSensorySignal PathwaySpecificityStressTechnical ExpertiseTherapeuticTissue SampleTransfer RNATransfer RNA AminoacylationTyrosine-tRNA LigaseUnited StatesWritingauditory pathwayaxon injurybasebiological adaptation to stresscareercell typedruggable targetflyhearing impairmentin vivoinduced pluripotent stem cellinsightkidney cellknock-downmembermitochondrial dysfunctionmouse modelmutantresponsesexspiral ganglionsymposiumtherapeutic developmenttranscriptome sequencing
项目摘要
PROJECT SUMMARY
Charcot-Marie-Tooth (CMT) disease is a genetically and clinically heterogeneous group of
inherited peripheral neuropathies that is characterized by damage to long motor and sensory
axons. The overall goal of this project is to identify the molecular and cellular processes that are
shared between different CMT genes to help address a common target for treatment for this
currently incurable disease. Our lab extensively studies aminoacyl-tRNA synthetases (aaRS),
the largest gene family involved in CMT, and discovered the nuclear function of one aaRS,
TyrRS, was shown to be associated to CMT pathogenesis while acting as a transcriptional
regulator under oxidative stress. Aim 1 sets out to understand how the nuclear aaRS function in
oxidative stress response plays a role in mouse physiology and if it is the commonality between
CMT-linked aaRS. Findings so far suggest nuclear TyrRS in mice leads to an increased
metabolism and disruption in the auditory system. This proposal sets out to perform a
longitudinal study to determine if the hearing loss is degenerative and where in the auditory
pathway there is a defect (e.g., sensory epithelium, spiral ganglion, brainstem, midbrain) while
also examining the molecular targets responsible using RNA-Sequencing on tissue samples.
Additionally, we uncovered that CMT-linked aaRS share a similar nuclear localization response
upon oxidative stress treatment in neuronal cells only. Aim 1 also sets out to investigate this
apparent cell type specificity, examine more cell lines, and evaluate the factor responsible for
the translocation property. More broadly, I want to understand the connection between multiple
CMT genes and subtypes to have a holistic view of the cellular organelles and signaling
pathways underlying CMT pathomechanisms. Therefore, in Aim 2 as a postdoctoral trainee I will
study a range of CMT proteins across subtypes of varying phenotypes. Patient derived, induced
pluripotent stem cells will be differentiated into two relevant CMT cell types for each mutant:
motor neurons and Schwann cells. Because there is evidence suggesting mitochondrial defects
and oxidative stress in some CMT subtypes, I will specifically investigate mitochondrial
morphology, dynamics, and function using imaging and cell-based assays, as well as, exploring
the levels of oxidate stress, stress-related damage, and potential pathways affected in CMT in a
cell type specific manner. During this proposal, activities such as teaching, writing workshops,
mastery of technical skills, and conference participation will be emphasized to equip me with the
professional development needed for an independent career in neuroscience.
项目概要
腓骨肌萎缩症 (CMT) 是一组遗传和临床异质性的疾病
遗传性周围神经病,其特征是长运动和感觉受损
轴突。该项目的总体目标是确定分子和细胞过程
不同 CMT 基因之间共享,以帮助解决该疾病的共同治疗目标
目前为不治之症。我们的实验室广泛研究氨酰基-tRNA 合成酶 (aaRS),
参与 CMT 的最大基因家族,并发现了一个 aaRS 的核功能,
TyrRS,被证明与 CMT 发病机制相关,同时充当转录因子
氧化应激下的调节剂。目标 1 旨在了解核 aaRS 如何在
氧化应激反应在小鼠生理学中发挥着重要作用,如果它是两者之间的共性
CMT 连接的 aaRS。迄今为止的研究结果表明,小鼠体内的核 TyrRS 会导致
新陈代谢和听觉系统的破坏。该提案旨在执行一项
纵向研究以确定听力损失是否是退行性的以及听觉的哪个部位
通路存在缺陷(例如感觉上皮、螺旋神经节、脑干、中脑)
还使用组织样本上的 RNA 测序来检查负责的分子靶点。
此外,我们发现 CMT 连接的 aaRS 具有相似的核定位反应
仅在神经元细胞中进行氧化应激处理。目标 1 也着手对此进行调查
明显的细胞类型特异性,检查更多细胞系,并评估负责的因素
易位性质。更广泛地说,我想了解多个之间的联系
CMT 基因和亚型可全面了解细胞器和信号传导
CMT 病理机制的潜在途径。因此,在目标2中,作为博士后实习生我将
研究一系列跨不同表型亚型的 CMT 蛋白。患者衍生、诱导
对于每个突变体,多能干细胞将分化为两种相关的 CMT 细胞类型:
运动神经元和雪旺细胞。因为有证据表明线粒体缺陷
和某些 CMT 亚型中的氧化应激,我将专门研究线粒体
使用成像和基于细胞的检测来研究形态、动力学和功能,以及探索
氧化应激水平、应激相关损伤以及 CMT 中受影响的潜在途径
细胞类型特定方式。在此提案期间,诸如教学、写作研讨会等活动,
将强调掌握技术技能和参加会议,以使我具备
神经科学领域独立职业所需的专业发展。
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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Julia Alexis Jones其他文献
Julia Alexis Jones的其他文献
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{{ truncateString('Julia Alexis Jones', 18)}}的其他基金
Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease
研究腓骨肌萎缩症的病理机制
- 批准号:
10658862 - 财政年份:2022
- 资助金额:
$ 3.48万 - 项目类别:
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