PATHOLOG-OMICS - ESSENTIAL TREMOR IN THE BROADER CONTEXT OF

病理组学 - 更广泛背景下的特发性震颤

基本信息

批准号：
10307348
负责人：
PHYLLIS L FAUST
金额：
$ 62.36万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-23 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307348
关键词：
PATHOLOG OMICS ESSENTIAL TREMOR BROADER

项目摘要

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).

在过去的5到8年中，我们已经确定了本质的一系列形态变化震颤（ET）小脑，主要集中在Purkinje细胞（PC）周围。发现与ET相关的病理学引起了极大的兴趣，但也引起了困难的问题。在原发性小脑神经退行性中也观察到了其中几种病理诸如脊椎小脑共济失调（SCAS）和多系统萎缩（MSA）之类的疾病，但这些变化发生的程度尚未正式研究或与等。有趣的是，小脑现在越来越涉及震颤的产生其他疾病，例如帕金森氏病（PD）和肌张力障碍，但他们的小脑病理是目前出乎意料。因此，存在较大的形态数据差距。在更重要的是我们最近进行了激光捕获显微解剖（LCM），以专门针对PC 促进ET中细胞特异性分子变化的精确评估。我们获得了高度通过直接测序RNA（RNA-Seq）从中分离出来的新型差异基因表达谱 ET与控制大脑的PC。我们确定了47个不同表达的成绩单，哪个代码为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PD，Dystonia，MSA和SCA中PC的分子生物学尚未是执行。这代表了第二个大分子数据差距。这个五年的提案，使用ET患者以及其他一系列其他患者的验尸组织小脑疾病有两个目标。具体目的1：进行详细的验尸研究小脑，将ET患者小脑的形态学变化与初级小脑退行性疾病（SCA和MSA）的患者以及患有震颤和小脑受累（PD和肌张力障碍）的神经疾病的患者。我们将组装160个大脑的初始发现样本（50 ET，25 SCA，15 MSA，30 PD，15 肌张力障碍，25个对照）以及160个大脑的重复样本，评估病理学几个小脑室的变化。量化的分层聚类分析变量将用于确定是否有定义的“ ET群集”以及定义其他四种疾病的簇。特定目的2：探索分子生物学以小脑介入和/或为特征的神经退行性疾病的PC 使用新型的LCM-RNA-Seq方法，我们将确定分子表达是否这些疾病中PC的变化相同或不同。对于这些新颖的分子研究，我们建议使用60个大脑（ET，SCA，MSA，PD，Dystonia，Controls的10个大脑）。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain Donation Decisions as Disease Specific Behaviors: An Elucidation of the Donation Process in the Context of Essential Tremor.

DOI：
10.5334/tohm.704
发表时间：
2022
期刊：
TREMOR AND OTHER HYPERKINETIC MOVEMENTS
影响因子：
2.2
作者：
Iglesias-Hernandez, Daniella;Berry, Diane;Hernandez, Nora;Louis, Elan D
通讯作者：
Louis, Elan D

Gene expression analysis of the cerebellar cortex in essential tremor.

DOI：
10.1016/j.neulet.2019.134540
发表时间：
2020-03-16
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Martuscello RT;Kerridge CA;Chatterjee D;Hartstone WG;Kuo SH;Sims PA;Louis ED;Faust PL
通讯作者：
Faust PL

Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor.

下橄榄核变性不会减轻特发性震颤的震颤。

DOI：
10.1186/s40673-018-0080-3
发表时间：
2018
期刊：
Cerebellum & ataxias
影响因子：
0
作者：
Louis,ElanD;Diaz,DanielTrujillo;Kuo,Sheng-Han;Gan,Shi-Rui;Cortes,EttyP;Vonsattel,JeanPaulG;Faust,PhyllisL
通讯作者：
Faust,PhyllisL

Clinicopathological correlates of pyramidal signs in multiple system atrophy.

DOI：
10.1002/acn3.51576
发表时间：
2022-07
期刊：
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
影响因子：
5.3
作者：
Lin, Chi-Ying R.;Viswanathan, Anisha;Chen, Tiffany X.;Mitsumoto, Hiroshi;Vonsattel, Jean P.;Faust, Phyllis L.;Kuo, Sheng-Han
通讯作者：
Kuo, Sheng-Han