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：
PHYLLIS L FAUST
金额：
$ 60.35万
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：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10346058
关键词：
Address Affect American Anatomy Autopsy Biochemical Biochemistry Brain Calcium Calcium Channel Cell physiology Cellular Stress Cerebellar Cortex Cerebellar Diseases Cerebellum Chronic Clinical DNA Sequence Alteration Data Disabled Persons Disease Endoplasmic Reticulum Essential Tremor Event Foundations Funding Generations Genetic High Prevalence Human Human Pathology Impairment Intention Tremor Kinetics Knowledge Lead Light Macromolecular Complexes Measurement Measures Modeling Molecular Morphology Mus National Institute of Neurological Disorders and Stroke Observational Study Parkinson Disease Pathologic Pathway interactions Patients Pattern Persons Pharmacology Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiology Play Point Mutation Population Property Purkinje Cells Research Research Personnel Role Ryanodine Receptor Calcium Release Channel Severities Site Slice Sorting - Cell Movement Specificity Synapses Testing Therapeutic Time Transcript Treatment Failure Tremor United States National Institutes of Health cell injury disability improved in vitro Assay in vivo insight mouse genetics mouse model nervous system disorder neuroimaging neuropathology neurotensin mimic 1 prevent targeted treatment therapeutic target therapy development transcriptome sequencing

Address Affect American Anatomy Autopsy Biochemical Biochemistry Brain Calcium Calcium Channel Cell physiology Cellular Stress Cerebellar Cortex Cerebellar Diseases Cerebellum Chronic Clinical DNA Sequence Alteration Data Disabled Persons Disease Endoplasmic Reticulum Essential Tremor Event Foundations Funding Generations Genetic High Prevalence Human Human Pathology Impairment Intention Tremor Kinetics Knowledge Lead Light Macromolecular Complexes Measurement Measures Modeling Molecular Morphology Mus National Institute of Neurological Disorders and Stroke Observational Study Parkinson Disease Pathologic Pathway interactions Patients Pattern Persons Pharmacology Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiology Play Point Mutation Population Property Purkinje Cells Research Research Personnel Role Ryanodine Receptor Calcium Release Channel Severities Site Slice Sorting - Cell Movement Specificity Synapses Testing Therapeutic Time Transcript Treatment Failure Tremor United States National Institutes of Health cell injury disability improved in vitro Assay in vivo insight mouse genetics mouse model nervous system disorder neuroimaging neuropathology neurotensin mimic 1 prevent targeted treatment therapeutic target therapy development transcriptome sequencing

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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/摘要基本震颤（ET）是最常见的震颤障碍，影响美国总人群的2.2％。 Et也是随着时间的流逝，震颤变得越来越严重。尽管患病率很高，但治疗。 ET的选择远非满意厂，部分原因是对疾病机制的不清楚，让许多患者残疾。通过长期NIH资助的努力收集Postmortem et Brains，我们已经鉴定出反映Purkinje细胞（PC）中细胞损伤的ET小脑中的形态变化。遗传学和神经病理学的最新融合证据已经确定了异常内质的作用 ET中的网状（ER）钙处理。具体而言，一个称为ryanodine受体1型的关键ER钙通道（RYR1），在小脑皮层中的PC中表达，经历特定位点的磷酸化，在此中状态变得漏水。我们发现ET小脑显着提高了磷酸化的RyR1，在控制或帕金森小脑中没有看到，在ET中产生慢性ER钙泄漏状态小脑。我们建立了一个具有RYR1中有点突变的小鼠模型，该模型构成了位点 - 特定的磷酸化，概括RyR1泄漏表型（RYR1-S2844D“漏水”小鼠），这是小鼠模型开发了小脑生理和渐进式ET样震颤的改变。这些发现支持这种异常的ER钙处理有助于震颤。但是，详细的机制如何异常钙处理导致震颤，是否可以使用其操纵来治疗震颤尚不清楚，这是治疗发展的主要障碍。为了解决这一知识差距，我们建议测试功能失调的ER钙处理的假设导致结构和生理变化小脑驱动震颤。在拟议的五年研究中，我们将使用两种鼠标模型（AIM 1，AIM 2）尸体后的人类和大脑（AIM 3）解决了ER钙处理对震颤产生的作用：目的1：我们将确定小脑PC中RyR1-Leaky的小脑PC的特定结构和物理变化如何小鼠在震颤出现和进展中发挥作用。目标2：我们将确定是否双向调制 ER钙处理改变RYR1裂变小鼠中的PC生理学和震颤，并检查PC的特异性这些改变。目标3：我们将确定RYR1生化重塑的上游调节器是否 RyR1泄漏程度在尸体后及其脑中有所改变，并将其关联震颤严重程度和PC病理变化的指标。这些数据将提高我们对ET的理解从观察性研究到机械洞察力，这将是治疗的科学原理发展。