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: 8301693
• 负责人: DAVID G. STANDAERT
• 金额: $ 38.15万
• 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/8301693
• 关键词: Acetylcholine; Address; Basal Ganglia; Behavior; Behavioral; Brain; Brain region; Cerebellum; Cerebral cortex; Corpus striatum structure; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dystonia; Dystonia Musculorum Deformans; Early Onset Dystonia; Etiology; Exhibits; Functional disorder; Genes; Genetically Engineered Mouse; Goals; Human; In Vitro; Interneurons; Knock-in Mouse; Measures; Microdialysis; Modeling; Molecular; Motor; Mutation; Neurons; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Population; Proteins; Resources; Rodent; Series; Site; Symptoms; TorsinA; Work; cholinergic; design; dopaminergic neuron; early onset; 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.

尽管导致 DYT1 肌张力障碍的基因在近十年前就被发现了，但其机制 这种或许多其他形式的肌张力障碍患者的症状的原因仍不确定。这是 合理设计有效疗法的主要障碍。在前期的支持期间，我们生产了 并鉴定了几种 DYT1 小鼠模型，其中存在异常 torsinA 的表达 蛋白质遍布整个大脑，并发现这些蛋白质同时表现出行为和神经化学 与人类疾病的某些方面相似的异常现象。这些都提供了重要的 深入了解突变体torsinA对大脑功能的影响。然而，这些模型并没有解决 异常蛋白质如何导致表型异常或确定作用位点的问题。在 在这个项目中，我们将制作和研究一系列新型小鼠模型，选择性灭活torsinA， 或 DYT1 突变的敲入。利用这些，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 DYT1 突变的选择性失活或敲入进一步缩小焦点 纹状体神经元群体和多巴胺能神经元内。该项目还将与 其他项目和核心，以确定开发其他新颖小鼠模型的机会。最后，我们将 通过评估已知对人类有效的药物治疗的效果来寻求验证这些模型 肌张力障碍，并建立一个国家资源来分发这些模型，以促进发展 新疗法。这项工作的总体目标是建立该组织的解剖部位和机制。 导致 DYT1 和其他肌张力障碍的功能障碍，并为该疾病提供靶向治疗。