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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：
10541251
负责人：
PHYLLIS L FAUST
金额：
$ 61.26万
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/10541251
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 Infusion procedures 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 Point Mutation Population Property Purkinje Cells Research Research Personnel Role Ryanodine Receptor Calcium Release Channel Severities Site Slice Sorting Specificity Spinocerebellar Ataxias 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

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