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:
    10210793
  • 负责人:
  • 金额:
    $ 102.83万
  • 依托单位:
  • 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

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.
特发性震颤(ET)是一种慢性进行性神经系统疾病,影响美国700万人

项目成果

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PHYLLIS L FAUST其他文献

PHYLLIS L FAUST的其他文献

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{{ truncateString('PHYLLIS L FAUST', 18)}}的其他基金

Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor
特发性震颤中靶向小脑内质网钙处理
  • 批准号:
    10346058
  • 财政年份:
    2021
  • 资助金额:
    $ 102.83万
  • 项目类别:
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
  • 批准号:
    10553702
  • 财政年份:
    2021
  • 资助金额:
    $ 102.83万
  • 项目类别:
Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor
特发性震颤中靶向小脑内质网钙处理
  • 批准号:
    10541251
  • 财政年份:
    2021
  • 资助金额:
    $ 102.83万
  • 项目类别:
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
  • 批准号:
    10378691
  • 财政年份:
    2021
  • 资助金额:
    $ 102.83万
  • 项目类别:
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
  • 批准号:
    10307348
  • 财政年份:
    2020
  • 资助金额:
    $ 102.83万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 102.83万
  • 项目类别:
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:
    9213399
  • 财政年份:
    2015
  • 资助金额:
    $ 102.83万
  • 项目类别:
Essential Tremor: Gene expression profiling in cerebellar Purkinje cells
特发性震颤:小脑浦肯野细胞的基因表达谱
  • 批准号:
    8226636
  • 财政年份:
    2011
  • 资助金额:
    $ 102.83万
  • 项目类别:
Essential Tremor: Gene expression profiling in cerebellar Purkinje cells
特发性震颤:小脑浦肯野细胞的基因表达谱
  • 批准号:
    8320096
  • 财政年份:
    2011
  • 资助金额:
    $ 102.83万
  • 项目类别:
CNS defects in a murine Zellweger syndrome model
小鼠齐薇格综合征模型中的中枢神经系统缺陷
  • 批准号:
    7237179
  • 财政年份:
    1999
  • 资助金额:
    $ 102.83万
  • 项目类别:

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