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（由适用提供）：在过去的5-8年中，我们确定了必需树（ET）小脑的形态学变化群，主要集中在Purkinje细胞（PC）周围。与ET相关的病理的发现引起了极大的兴趣，但也引发了困难的问题。在原发性小脑神经退行性疾病中也观察到了其中几种病理学，例如脊椎发展（SCAS）和多个系统萎缩（MSA），但是这些变化发生的程度尚未正式研究或与ET中的ET相比。有趣的是，现在越来越多的小脑在其他疾病（例如帕金森氏病（PD）和肌张力障碍）中的震颤产生中实施，但它们的小​​脑病理学出乎意料。因此，存在较大的形态数据差距。在更一级的层面上，我们最近进行了激光捕获显微解剖（LCM），以专门针对PC，从而支持细胞的精确评估 ET中的特定分子变化。我们通过从ET与对照大脑的PC分离的RNA（RNA-SEQ）的直接测序获得了高度新颖的差异基因表达谱。我们确定了47个不同表达的转录本，这些转录本为调节神经元功能的蛋白质代码。但是，尚未进行一组平行的LCM-RNA-Seq研究，探索PD，肌张力障碍，MSA和SCA中PC的分子生物学。这代表了第二个大分子数据差距。该五年的建议使用了ET患者的死后组织以及其他各种小脑疾病的患者，其目标有两个。具体目的1：对小脑进行详细的验尸研究，将ET患者小脑的形态学变化与原发性小脑退行性疾病（SCA和MSA）的患者的形态学变化以及震颤和小脑介入（PD和pd和dystonia）的神经疾病患者的患者。我们将组装160个大脑（50 ET，25 SCA，15 MSA，30 PD，15肌张力障碍，25个对照）的初始发现样本以及160个大脑的重复样本，评估了几个小脑室中患者的变化。量化变量的层次群集分析将用于确定是否有其他四种疾病中的每个疾病有定义的“ ET群集”以及定义的簇。特定目的2：探索以小脑介入和/或震颤为特征的神经退行性疾病中PC的分子生物学。使用新型的LCM-RNA-seq方法，我们将确定PC中的分子表达变化在这些疾病中是否相同或不同。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，肌张力障碍，对照中的10个大脑）。