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
基本信息
- 批准号:10346058
- 负责人:
- 金额:$ 60.35万
- 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:2021-12-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAmericanAnatomyAutopsyBiochemicalBiochemistryBrainCalciumCalcium ChannelCell physiologyCellular StressCerebellar CortexCerebellar DiseasesCerebellumChronicClinicalDNA Sequence AlterationDataDisabled PersonsDiseaseEndoplasmic ReticulumEssential TremorEventFoundationsFundingGenerationsGeneticHigh PrevalenceHumanHuman PathologyImpairmentIntention TremorKineticsKnowledgeLeadLightMacromolecular ComplexesMeasurementMeasuresModelingMolecularMorphologyMusNational Institute of Neurological Disorders and StrokeObservational StudyParkinson DiseasePathologicPathway interactionsPatientsPatternPersonsPharmacologyPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPlayPoint MutationPopulationPropertyPurkinje CellsResearchResearch PersonnelRoleRyanodine Receptor Calcium Release ChannelSeveritiesSiteSliceSorting - Cell MovementSpecificitySynapsesTestingTherapeuticTimeTranscriptTreatment FailureTremorUnited States National Institutes of Healthcell injurydisabilityimprovedin vitro Assayin vivoinsightmouse geneticsmouse modelnervous system disorderneuroimagingneuropathologyneurotensin mimic 1preventtargeted treatmenttherapeutic targettherapy developmenttranscriptome sequencing
项目摘要
PROJECT SUMMARY/ ABSTRACT
Essential tremor (ET) is the most common tremor disorder, affecting 2.2% of the total US population. ET is also
a progressive disorder, with tremor becoming more severe over time. Despite its high prevalence, therapeutic
options for ET are far from satisfactory, in part due to an unclear understanding of disease mechanisms,
leaving many patients disabled. Through long-term NIH funded efforts to collect postmortem ET brains, we
have identified morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs).
Recent converging evidence of genetics and neuropathology has identified a role for abnormal endoplasmic
reticulum (ER) calcium handling in ET. Specifically, a key ER calcium channel called ryanodine receptor type 1
(RyR1), which is expressed in PCs in cerebellar cortex, undergoes site-specific phosphorylation and in this
state becomes leaky. We found that ET cerebellum has markedly increased levels of phosphorylated RyR1,
which is not seen in control or Parkinson’s cerebellum, creating a chronic ER calcium leak state in the ET
cerebellum. We established a mouse model harboring a point mutation in RyR1 that mimics constitutive site-
specific phosphorylation, recapitulating the RyR1 leaky phenotype (RyR1-S2844D “leaky” mice), and this
mouse model develops altered cerebellar physiology and progressive ET-like tremor. These findings support
that abnormal ER calcium handling contributes to tremor. However, the detailed mechanism how abnormal ER
calcium handling leads to tremor and whether its manipulation can be used to treat tremor remains unclear,
which is a major obstacle for therapy development. Towards solving this knowledge gap, we propose to test
the hypothesis that dysfunctional ER calcium handling leads to structural and physiological alterations in
cerebellum that drive tremor. In the proposed five year study, we will use both mouse models (Aim 1, Aim 2)
and postmortem human ET brains (Aim 3) to address the role of ER calcium handling for tremor generation:
Aim 1: We will determine how specific structural and physiological changes in cerebellar PCs of RyR1-leaky
mice play a role in tremor emergence and progression. Aim 2: We will determine if bi-directional modulation of
ER calcium handling alters PC physiology and tremor in RyR1-leaky mice and examine the PC specificity of
these alterations. Aim 3: We will determine whether the upstream regulators for RyR1 biochemical remodeling
and the degree of RyR1 leakiness are altered in the postmortem human ET cerebellum and correlate these
metrics with tremor severity and PC pathologic changes. These data will advance our understanding of ET
from observational studies into mechanistic insight, which will serve as scientific rationale for therapy
development.
项目摘要/摘要
原发性震颤(ET)是最常见的震颤障碍,占美国总人口的2.2%。ET也是
一种进行性疾病,随着时间的推移,震颤变得更加严重。尽管它的发病率很高,但具有治疗作用
ET的选择远远不能令人满意,部分原因是对疾病机制的了解不清,
导致许多患者残废。通过美国国立卫生研究院长期资助的收集死后ET大脑的努力,我们
已发现ET小脑的形态变化反映了浦肯野细胞(PC)的细胞损伤。
最近遗传学和神经病理学的融合证据已经确定了内质异常的作用
网织(ER)钙在ET中的处理。具体地说,一个关键的内质网钙通道称为兰尼定受体1型
(RyR1)在小脑皮质的PC中表达,经历了位点特异性的磷酸化,并在
国家变得漏洞百出。我们发现,ET小脑显著增加了磷酸化RyR1的水平,
这在对照组或帕金森氏症小脑中未见,在ET中造成慢性内质网钙泄漏状态
小脑。我们建立了一种小鼠模型,该模型在RyR1中含有模拟构成部位的点突变-
特异性磷酸化,重述RyR1泄漏表型(RyR1-S2844D“泄漏”小鼠),以及这
小鼠模型出现小脑生理改变和进行性ET样震颤。这些发现支持
内质网钙离子处理异常导致震颤。然而,ER的详细机制如何异常
钙离子处理会导致震颤,其处理方法是否可以用于治疗震颤尚不清楚。
这是治疗发展的一个主要障碍。为了解决这一知识鸿沟,我们建议测试
内质网钙调节功能障碍导致心肌细胞结构和生理改变的假说
推动震颤的小脑。在拟议的五年研究中,我们将使用两种小鼠模型(目标1,目标2)
和死后人类ET大脑(目标3),以解决内质网钙处理在震颤产生中的作用:
目标1:我们将确定RyR1-Leaky小脑PC的特定结构和生理变化
老鼠在震颤的出现和发展中扮演着重要的角色。目标2:我们将确定双向调制是否
内质网钙处理改变RyR1泄漏小鼠的PC生理和震颤,并检测PC的特异性
这些变化。目的3:我们将确定RyR1生化重塑的上游调节因子是否
和RyR1的漏失程度在死后的人类ET小脑中发生变化并与这些变化相关
震颤严重程度和PC病理改变的指标。这些数据将促进我们对ET的理解
从观察性研究到机械洞察力,这将成为治疗的科学理论基础
发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('PHYLLIS L FAUST', 18)}}的其他基金
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:
10210793 - 财政年份:2021
- 资助金额:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 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:
$ 60.35万 - 项目类别:
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