Brain regions and genes implicated in early onset dystonia

与早发性肌张力障碍有关的大脑区域和基因

• 批准号: 7798732
• 负责人: DAVID G. STANDAERT
• 金额: $ 33.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7798732
• 关键词: Acetylcholine; Address; Basal Ganglia; Behavior; Behavioral; Brain; Brain region; Cerebellum; Cerebral cortex; Corpus striatum structure; Development; Disease; Dopamine; Dopamine D2 Receptor; Dystonia; Early Onset Dystonia; Exhibits; Functional disorder; Genes; Genetically Engineered Mouse; Goals; Human; In Vitro; Interneurons; Knock-in Mouse; Measures; Microdialysis; Modeling; Motor; Mutation; Neurons; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Population; Proteins; Resources; Rodent; Series; Site; Symptoms; TorsinA; Work; cholinergic; design; dopaminergic neuron; effective therapy; human disease; in vivo; insight; motor learning; mouse model; mutant; nervous system disorder; neurochemistry; novel

Although the gene which causes DYT1 dystonia was discovered nearly a decade ago, the mechanism responsible for the symptoms in patients with this or many other forms of dystonia remains uncertain. This is a major obstacle to the rational design of effective therapies. During the prior period of support, we produced and characterized several mouse models of DYT1 in which there is expression of the abnormal torsinA protein throughout the brain, and found that these exhibit both behavioral as well as neurochemical abnormalities which appear to resemble aspects ofthe human disease. These have provided important insight into the effects of mutant torsinA on brain function. These models do not, however, resolve the question of how the abnormal protein leads to the phenotypic abnormalities, or identify the site of action. In this project, we will produce and study a novel series of mouse models with selective inactivation of torsinA, or knock-in ofthe DYT1 mutation. Using these, we will address the issue of whether selective inactivation in the cortex, striatum, or cerebellum is sufficient to produce behavioral and neurochemical abnormalities in the intact rodent. Given the strong evidence for involvement of the basal ganglia in many forms of dystonia, we will narrow the focus further by examining selective inactivation or knock-in ofthe DYT1 mutation in populations of striatal neurons, and within dopaminergic neurons. This project will also work closely with the other projects and cores, to identify opportunities to develop additional novel mouse models. Finally, we will seek to validate these models by assessing the effect of a drug treatment known to be effective in human dystonia, and establish a National Resource for distribution of these models to promote development of novel therapies. The overall goal of this work is to establish the anatomical site and mechanism of the dysfunction responsible for DYT1 and other dystonias, and enable targeted therapies for the disease.

虽然导致DYT 1肌张力障碍的基因在近十年前就被发现了，但其机制 导致这种或许多其他形式的肌张力障碍患者症状的原因仍然不确定。这是 这是合理设计有效疗法的主要障碍。在上一个支持期间，我们制作了 并表征了几种DYT 1小鼠模型，其中存在异常扭转蛋白A的表达， 蛋白质，并发现这些表现出行为以及神经化学 这些异常看起来与人类疾病的某些方面相似。这些提供了重要的 研究变异型扭转蛋白A对大脑功能的影响然而，这些模型并不能解决 异常蛋白质如何导致表型异常的问题，或确定作用位点。在 本项目将建立和研究一系列选择性失活torsinA的小鼠模型， 或敲入DYT1突变。使用这些，我们将解决是否选择性失活的问题， 皮质、纹状体或小脑足以在大脑中产生行为和神经化学异常。 完整的啮齿动物鉴于有强有力的证据表明基底神经节参与多种形式的肌张力障碍，我们 将通过检查选择性失活或敲入DYT1突变进一步缩小焦点， 纹状体神经元群和多巴胺能神经元内。该项目还将与 其他项目和核心，以确定开发其他新型小鼠模型的机会。最后我们将 试图通过评估已知对人类有效的药物治疗的效果来验证这些模型 肌张力障碍，并建立一个国家资源分配这些模型，以促进发展， 新疗法这项工作的总体目标是建立的解剖部位和机制， 该研究的目的是研究导致DYT1和其他肌张力障碍的功能障碍，并使针对该疾病的靶向治疗成为可能。