Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration
Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration
批准号:
10210793
负责人:
PHYLLIS L FAUST
金额:
$102.83万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-01 至 2026-01-31
关键词:
AffectAgeAmericanAnatomyAnimal ModelAutopsyBiologicalBiological ProcessBrainBrain regionCase StudyCatalogsCell NucleusCerebellar CortexCerebellar NucleiCerebellumChoreaChronicClinicalCollectionComplementDataDentate nucleusDiseaseDisease modelDystoniaEssential TremorEventGeneticGenomicsHarvestIndividualInferiorKnowledgeMapsMass Spectrum AnalysisMethodsMolecularMotor CortexNerve DegenerationNeurologicNeuronsOlives - dietaryOrganPathogenesisPathologicPathologyPathway interactionsPatientsPatternPhenotypePhysiologicalPopulationPostmortem ChangesProteomeProteomicsPublishingPurkinje CellsRed nucleus structureSamplingSiteStructureSurfaceSynaptic TransmissionTestingThalamic structureTissuesTremoraxon guidancebasecell typeclinical phenotypeexperimental studyhuman diseasehuman tissueinsightlaser capture microdissectionmind controlnervous system disorderneuropathologyprotein expressionrepositorytranscriptometranscriptome sequencing
中文摘要
特发性震颤(ET)是一种慢性和进行性神经系统疾病,影响700万人,
美国,使其成为最常见的震颤障碍。尽管如此普遍,其潜在的病理机制
仍然是个谜在2003年,我们建立了原发性震颤集中大脑知识库。细致
脑供体的临床表型确定之后是脑收获和严格的死后表征。
通过这种机制,我们已经收获了217个ET大脑,代表了迄今为止最大的ET收集
世界上最聪明的人通过详细的、系统的、受控的死后研究,我们了解到,
ET的主要死后变化位于小脑中,集中在浦肯野细胞中/周围。然而,在基本
我们的研究只是触及了表面。事实上,我们的研究只对一个副热带地区进行了取样,
小脑皮层的一部分作为一个器官,小脑不是一个单一的实体;它是异质的,
明确定义的解剖和功能区室,这些区室在各种疾病中有差异
states.我们还没有绘制出ET小脑中所见的退化模式(Aim 1)。当前
疾病模型也非常以小脑为中心,必须考虑问题是否更广泛。的确,
存在“震颤回路”,小脑-丘脑-皮质(CTC)回路和橄榄-小脑(OC)网络,
包括小脑、脑深部结构和运动皮层之间的高度组织化的连接,
以及小脑和下橄榄核之间;这些网络被认为参与了起源,
在ET中传播震颤。死亡后ET的变化是否分布在和/或差异
对这些生理网络的影响尚不清楚(目标2)。对ET的研究也必须从
从细胞变化到分子变化为了开始定义ET的分子特征,过去
几年来,我们通过RNA测序探索了ET小脑的分子转录组,
在四个主要的生物途径中发现了失调。因此,为了补充我们对转录组的研究,
我们现在提出了一种基于质谱的蛋白质组学方法,
显微切割(LCM)以靶向震颤回路中的不同神经元群体。蛋白质组的创建
目录,比较病例和匹配的对照,将揭示与以下疾病特别相关的分子事件:
疾病(目标3)。这项为期五年的研究有三个目标。目标1:创建一个精细的
ET小脑神经病理学。我们将确定是否以及以何种模式的退行性变化,
已经证明,在新小脑的一个区域延伸到其他功能/解剖小脑区域。
目的2:确定ET的退行性改变是否局限于小脑或更广泛
涉及CTC环和OC环中的其他结构。目的3:使用基于质谱的蛋白质组学
方法来研究蛋白质表达在ET中以公正的方式。我们将分析整个小脑皮层
组织,并与LCM合作,靶向浦肯野细胞以及齿状核和下橄榄核中的神经元。
英文摘要
Essential tremor (ET) is a chronic and progressive neurological disease affecting 7 million individuals in the
US, making it the most common tremor disorder. Despite being so prevalent, its underlying patho-mechanisms
remain enigmatic. In 2003, we established the Essential Tremor Centralized Brain Repository. Meticulous
clinical phenotyping of brain donors is followed by brain harvest and rigorous postmortem characterization.
Through this mechanism, we have harvested 217 ET brains, representing by far the largest collection of ET
brains in the world. Through detailed, systematic, controlled postmortem studies, we have learned that the
major postmortem changes in ET lie in the cerebellum, centered in/around Purkinje cells. Yet, in fundamental
ways, our studies have only grazed the surface. Indeed, our studies have sampled only one parasagittal region
of the cerebellar cortex. As an organ, the cerebellum is not a unitary entity; it is heterogeneous and comprised
of well-defined anatomic and functional compartments, which are differentially involved across various disease
states. We have yet to map out the degenerative pattern seen in the ET cerebellum (Aim 1). The current
disease model is also very cerebellar-centric, and one must consider whether the problem is wider. Indeed,
there is a “tremor circuit”, the cerebello-thalamo-cortical (CTC) loop and olivo-cerebellar (OC) networks,
comprising highly organized connections between the cerebellum, deep brain structures and the motor cortex,
and between cerebellum and inferior olive; these networks have been posited to be involved in the origins and
propagation of tremor in ET. Whether the postmortem changes in ET are distributed across and/or differentially
affects these physiological networks is not known (Aim 2). Studies of ET must also move from the level of
cellular changes down to molecular events. To begin to define the molecular features of ET, over the past
several years we have explored the molecular transcriptome in ET cerebellum by RNA sequencing, which
identified dysregulation in four main biologic pathways. Thus, to complement our studies of the transcriptome,
we now propose a mass spectrometry-based proteomics approach, and partnering this with laser capture
microdissection (LCM) to target distinct neuronal populations in the tremor circuit. The creation of proteome
catalogs, comparing cases to matched controls, will uncover molecular events specifically associated with
disease (Aim 3). The proposed five-year study has three aims. AIM 1: To create a granular and refined map of
ET cerebellar neuropathology. We will determine whether and in what pattern the degenerative changes we
have documented in one region of the neocerebellum extend to other functional/anatomic cerebellar regions.
AIM 2: To determine whether the degenerative changes in ET are restricted to the cerebellum or more broadly
involve other structures in the CTC loop and OC loop. AIM 3: To use a mass spectrometry-based proteomic
approach to study protein expression in ET in an unbiased manner. We will analyze whole cerebellar cortex
tissue and partner this with LCM to target Purkinje cells as well as neurons in dentate and inferior olive nuclei.
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