Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration

深入探讨：绘制特发性震颤的神经病理学并探索神经退行性变的分子基础

基本信息

批准号：
10378691
负责人：
PHYLLIS L FAUST
金额：
$ 99.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378691
关键词：
Affect Age American Anatomy Animal Model Autopsy Biological Biological Process Brain Brain region Case Study Catalogs Cell Nucleus Cerebellar Cortex Cerebellar Nuclei Cerebellum Chorea Chronic Clinical Collection Complement Data Dentate nucleus Disease Disease model Dystonia Essential Tremor Event Genetic Genomics Harvest Individual Inferior Knowledge Maps Mass Spectrum Analysis Methods Molecular Motor Cortex Nerve Degeneration Neurologic Neurons Olives - dietary Organ Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phenotype Physiological Population Postmortem Changes Proteome Proteomics Publishing Purkinje Cells Red nucleus structure Sampling Site Structure Surface Synaptic Transmission Testing Thalamic structure Tissues Tremor axon guidance base cell type clinical phenotype experimental study human disease human tissue insight laser capture microdissection mind control nervous system disorder neuropathology protein expression repository transcriptome transcriptome sequencing

项目摘要

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.

Essential Tree（ET）是一种慢性和进行性神经系统疾病，影响700万个人我们，使其成为最常见的树木障碍。尽管如此普遍，但其基本的病情机制保持神秘。 2003年，我们建立了基本的震颤集中式大脑存储库。细致脑捐献者的临床表型之后是脑收获和严格的死后表征。通过这种机制，我们收集了217 et脑，代表了迄今为止最大的ET集合世界上的大脑。通过详细的，系统的，受控的验尸研究，我们了解到 ET的重大验尸变化位于小脑中，以宾夕法尼亚细胞为中心。但是，基本方式，我们的研究只能放牧表面。确实，我们的研究仅取样了一个副臂区域小脑皮层。作为器官，小脑不是一个统一的实体。它是异质的，完成了定义明确的解剖和功能隔室，它们在各种疾病中都不同国家。我们尚未绘制出在Et小脑中看到的退化模式（AIM 1）。电流疾病模型也以小脑为中心，必须考虑问题是否更广泛。的确，有一个“ Tremori电路”，小脑 - thalamo-cortical（CTC）环和Olivo-Cerebellar（OC）网络，包括小脑，深脑结构和运动皮层之间的高度组织连接，在小脑和下橄榄之间；这些网络已被固定在起源和 ET中震颤的传播。 ET中验尸变化是否分布在和/或差异上影响这些物理网络尚不清楚（AIM 2）。 ET的研究也必须从细胞变化为分子事件。开始定义ET的分子特征几年来，我们通过RNA测序探索了ET小脑中的分子转录组，该测序在四个主要的生物学途径中鉴定出失调。为了补充我们对转录组的研究，现在，我们提出了一种基于质谱的蛋白质组学方法，并将其与激光捕获合作微分解（LCM）靶向树回路中不同的神经元种群。蛋白质组的创建目录，将案例与匹配对照进行比较，将发现与分子事件特别相关的分子事件疾病（目标3）。拟议的五年研究有三个目标。目的1：创建一个颗粒状和精制图 Et小脑神经病理学。我们将确定我们的退化性变化是否以及如何以什么方式已经记录在新脑的一个区域中，扩展到其他功能/解剖小脑区域。目标2：确定ET的退化变化是否仅限于小脑还是更广泛涉及CTC循环和OC循环中的其他结构。目标3：使用基于质谱的蛋白质组学以公正的方式研究ET中蛋白质表达的方法。我们将分析整个小脑皮质组织并与LCM合作，以靶向Purkinje细胞以及齿状和下橄榄核中的神经元。