PATHOLOG-OMICS - ESSENTIAL TREMOR IN THE BROADER CONTEXT OF NEURODEGENERATION

病理组学 - 神经退行性更广泛背景下的特发性震颤

• 批准号: 8995706
• 负责人: PHYLLIS L FAUST
• 金额: $ 65.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-05 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995706
• 关键词: Age; Autopsy; Axon; Biology; Brain; Brain region; Candidate Disease Gene; Carrier Proteins; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellar cortex structure; Cerebellum; Cluster Analysis; Code; Collection; Data; Data Set; Degenerative Disorder; Dendrites; Disease; Dystonia; Essential Tremor; Evaluation; Event; Excitatory Amino Acid Transporter 2; Fiber; Gene Expression; Gene Expression Profile; Generations; Glutamate Transporter; Human; Idiopathic Parkinson Disease; Leucine-Rich Repeat; Methods; Molecular; Molecular Biology; Multiple System Atrophy; Myoepithelial cell; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Output; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Process; Proteins; Purkinje Cells; RNA Sequences; Recurrence; STC1 gene; Sampling; Series; Spinocerebellar Ataxias; Swelling; Synapses; Techniques; Tissues; Torpedo; Transcript; Tremor; axonal sprouting; base; brain tissue; density; differential expression; interest; laser capture microdissection; mind control; nervous system disorder; novel; profiles in patients; public health relevance; response to injury; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Over the past 5 - 8 years, we have identified a cluster of morphological changes in the essential tremor (ET) cerebellum, predominantly centered in/around the Purkinje cell (PC). The discovery of ET-related pathology has generated great interest but it has also raised difficult questions. Several of these pathologies have also been observed in primary cerebellar neurodegenerative diseases such as spinocerebellar ataxias (SCAs) and multiple system atrophy (MSA), but the degree to which these changes occur has not been formally studied or compared with that in ET. Interestingly, the cerebellum is now increasingly being implicated in tremor generation in other diseases such as Parkinson's disease (PD) and dystonia, yet their cerebellar pathology is presently unexplored. Hence, there is a large morphologic data gap. On a more primary level, we recently performed laser-capture microdissection (LCM) to specifically target PCs, thereby facilitating a precise evaluation of cell specific molecular changes in ET. We obtained a highly novel differential gene expression profile by direct sequencing of RNA (RNA-seq) isolated from PCs of ET vs. control brains. We identified 47 differentially expressed transcripts, which code for proteins that regulate neuronal function. However, a parallel set of LCM-RNA-seq studies, exploring the molecular biology of PCs in PD, dystonia, MSA and SCA, have yet to be performed. This represents a second, large molecular, data gap. This five-year proposal, which uses postmortem tissue from patients with ET well as from patients with a range of other cerebellar disorders, has two aims. Specific Aim 1: To undertake detailed postmortem studies of the cerebellum, comparing morphological changes in the cerebellum of ET patients to those of patients with primary cerebellar degenerative diseases (SCA and MSA) as well as those of patients with neurological diseases with tremor and cerebellar involvement (PD and dystonia). We will assemble an initial discovery sample of 160 brains (50 ET, 25 SCA, 15 MSA, 30 PD, 15 dystonia, 25 controls) as well as a replicate sample of 160 brains, assessing pathological changes across several cerebellar compartments. Hierarchical cluster analysis of quantified variables will be used to determine whether there is a definable "ET cluster" as well as definable clusters for each of these other four diseases. Specific Aim 2: To explore the molecular biology of PCs across neurodegenerative diseases characterized by cerebellar involvement and/or tremor. Using a novel LCM-RNA-seq approach, we will determine whether molecular expression changes in PCs are the same or differ across these diseases. For these novel molecular studies, we propose to use 60 brains (10 each of ET, SCA, MSA, PD, dystonia, controls).

 描述(申请人提供)：在过去的5-8年里，我们发现了一组特发性震颤(ET)小脑的形态变化，主要集中在浦肯野细胞(PC)内/周围。ET相关病理的发现引起了人们的极大兴趣，但也提出了一些棘手的问题。在脊髓小脑性共济失调(SCAS)和多系统萎缩(MSA)等原发性小脑神经退行性疾病中也观察到了其中几种病理变化，但这些变化的发生程度尚未正式研究，也未与ET进行比较。有趣的是，小脑现在越来越多地与帕金森病(PD)和肌张力障碍等其他疾病的震颤产生有关，但它们的小脑病理目前尚不清楚。因此，存在很大的形态数据差距。在更初级的层面上，我们最近进行了激光捕获显微解剖(LCM)，专门针对PC，从而促进了对细胞的准确评估 ET中的特异性分子变化。我们通过直接测序从ET和对照组的PC中分离的RNA(RNA-seq)获得了一个高度新颖的差异基因表达谱。我们鉴定了47个差异表达的转录本，这些转录本编码调节神经元功能的蛋白质。然而，一组平行的LCM-RNA-SEQ研究，探索PC在PD、肌张力障碍、MSA和SCA中的分子生物学，尚未进行。这代表着第二个大分子数据鸿沟。这项为期五年的计划使用了ET患者以及其他一系列小脑疾病患者的尸检组织，有两个目标。具体目的1：对小脑进行详细的尸检，比较ET患者与原发性小脑退行性疾病(SCA和MSA)以及伴有震颤和小脑受累的神经系统疾病(PD和肌张力障碍)患者小脑的形态变化。我们将收集160个大脑(50个ET，25个SCA，15个MSA，30个PD，15个肌张力障碍，25个对照)的初步发现样本，以及160个大脑的重复样本，评估几个小脑区的病理变化。量化变量的等级聚类分析将被用来确定是否存在可定义的“ET簇”以及这四种疾病中的每一种疾病的可定义簇。具体目的2：探讨PC在以小脑受累和/或震颤为特征的神经退行性疾病中的分子生物学。使用一种新的LCM-RNA-SEQ方法，我们将确定PC中分子表达的变化在这些疾病中是相同的还是不同的。对于这些新的分子研究，我们建议使用60个大脑(ET、SCA、MSA、PD、肌张力障碍和对照组各10个)。