Eukaryotic Initiation Factor 2a Signaling in Dystonia Pathogenesis and Treatment

肌张力障碍发病机制和治疗中的真核起始因子 2a 信号转导

• 批准号: 9192708
• 负责人: Joseph Edward Rittiner
• 金额: $ 5.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192708
• 关键词: ATF2 gene; ATP phosphohydrolase; Accounting; Adverse effects; Animal Model; Biological; Biological Assay; Brain; Brain region; Cell Fractionation; Cell model; Cells; Childhood; Corpus striatum structure; Data; Disease; Dose; Dystonia; Dystonia Musculorum Deformans; Electrophysiology (science); Eukaryotic Cell; Eukaryotic Initiation Factors; Feedback; Fibroblasts; Genes; Genetic; Genetic Transcription; Glutamic Acid; Health; Homeostasis; Human; Human Genetics; Inherited; Laboratories; Lead; Light; Long-Term Depression; Measurement; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Motor; Movement Disorders; Mus; Mutation; Neurons; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Posture; Process; Proteins; Protocols documentation; Quality of life; RNA interference screen; Role; Scientific Advances and Accomplishments; Signal Transduction; Slice; Sporadic Dystonias; Stress; Symptoms; Synapses; Synaptic plasticity; System; TOR1A gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; TorsinA; Transcript; Translations; Up-Regulation; Western Blotting; Wild Type Mouse; Work; base; biological adaptation to stress; brain dysfunction; cellular pathology; early onset; exome sequencing; high throughput screening; improved; in vivo; inhibitor/antagonist; motor disorder; motor impairment; mouse model; mutant; novel; research study; response; stressor; symptom treatment; transcription factor; whole genome

ABSTRACT Dystonia, a debilitating movement disorder characterized by sustained and painful involuntary postures, is the 3rd most common movement disorder yet very little is known about its biological cause. Currently, only symptomatic treatments are available, which have limited efficacy, significant side effects, and are often invasive or require access to specialized facilities. Early-onset torsion dystonia (DYT1), the most common inherited form of dystonia, is a severe, childhood-onset form of the disease. Recently, our lab conducted a whole-genome RNAi screen using a novel assay of DYT1 cellular pathology, which identified Eukaryotic lnitiation Factor 2α (elF2α) signaling as the most highly enriched pathway. ln subsequent experiments, our lab showed that a compound which enhances elF2α signaling improved the DYT1 cellular pathology and a compound which inhibits elF2α signaling worsened the pathology in a dose-dependent manner, indicating that enhancing elF2α signaling is protective against DYT1 and vice versa. DYT1-isogenic model mice are deficient in a synaptic process known to require elF2α signaling and fibroblast cells derived from DYT1 patients display decreased elF2α signaling in response to stress stimulation, suggesting that elF2α signaling is deficient in DYT1 in vivo. Furthermore, mutations in both an upstream activator and a downstream effector of elF2α signaling are found in patients with other forms of dystonia, suggesting that defective elF2α signaling is critical in non-DYT1 dystonia pathogenesis as well. Therefore, l hypothesize that deficient elF2α signaling is a critical mediator of dystonia pathogenesis and that pharmacologically enhancing elF2α signaling will have therapeutic effects in animal models of dystonia. Here l propose to: 1) Determine how elF2α signaling is disrupted in DYT1 by a) measuring neuronal elF2α signaling in wild type and DYT1 model mice and b) determining how the DYT1-causative mutation leads to deficient elF2α signaling. 2) Determine if enhancing elF2α signaling reverses a synaptic plasticity deficit in DYT1 model mice using slice electrophysiology. 3) Determine if inhibiting elF2α signaling is sufficient to cause dystonic phenotypes in wild-type mice, either alone or in conjunction with environmental stress.

抽象的 Dystonia是一种以持续和痛苦的非自愿位置为特征的使人衰弱的运动障碍，是第三种最常见的运动障碍，但对其生物学原因几乎没有知识。当前，只有有症状治疗，有效性有限，副作用明显，并且通常具有侵入性或需要使用专用设施。早期发作的扭曲肌张力纳（DYT1）是肌张力障碍最常见的形式，是一种严重的童年发作的疾病形式。最近，我们的实验室使用了DYT1细胞病理学的新测定法进行了全基因组RNAi筛选，该测定法认为真核lNitiation因子2α（ELF2α）信号传导是最富集的途径。在随后的实验中，我们的实验室表明，增强ELF2α信号传导的化合物改善了DYT1细胞病理学和一种抑制ELF2α信号传导的化合物，以剂量依赖性的方式使病理恶化，这表明增强ELF2α信号受到DYT1和VICE VERSA的保护。 Dyt1-异源模型小鼠在已知需要ELF2α信号传导的突触过程中确定性，而源自DYT1患者的成纤维细胞细胞对应激刺激的响应显示出改善的ELF2α信号传导，这表明ELF2α信号在VIVO中在Dyt1中是确切的。此外，在其他形式的肌张力障碍患者中发现了上游激活剂和ELF2α信号的下游效应子的突变，这表明ELF2α信号传导在非DYT1 dyt1 dystonia发病机理中也至关重要。因此，假设缺乏ELF2α信号传导是肌张力障碍发病机理的关键介质，并且药物增强ELF2α信号传导将在肌张力障碍动物模型中具有治疗作用。在这里提出：1）通过a）测量野生型和dyt1模型小鼠中的神经元ELF2α信号传导以及b）确定dyt1-促性突变如何导致缺乏ELF2α信号传导来确定DYT1中如何禁用ELF2α信号传导。 2）确定增强ELF2α信号传导是否会使用切片电生理学逆转DYT1模型小鼠中的合成可塑性不足。 3）确定抑制ELF2α信号是否足以在野生型小鼠中引起肌张力型表型，无论是单独还是与环境应力结合。