Brain TorsinA and childhood-onset Dystonia

Brain TorsinA 和儿童期发病的肌张力障碍

基本信息

批准号：
7647593
负责人：
PULLANIPALLY SHASHIDHARAN
金额：
$ 1.5万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647593
关键词：
Address Affect Animals Base Pairing Behavioral Brain Brain region Breeding Cell Nucleus Cells Child Childhood Childhood Onset Dystonias Chromosome Mapping Chromosomes, Human, Pair 9 Condition Corpus striatum structure Cultured Cells DYT1 gene Data Dendrites Development Disease Dopamine Dyskinetic syndrome Dystonia Electron Microscopy Electrophysiology (science)Exhibits Exocytosis Functional disorder Glutamates Glutamic Acid Goals Human Hyperactive behavior Inclusion Bodies Investigation Knockout Mice Knowledge Laboratories Lead Microdialysis Modeling Movement Disorders Mus Muscle Contraction Mutation Nerve Neuron-Specific Enolase Neurons Neurotransmitters Pathology Patients Pattern Phenotype Play Positioning Attribute Posture Protein Overexpression Proteins Public Health Purpose Rattus Role SNAPIN gene Screening procedure Specific qualifier value Structure Substantia nigra structure Synapses Synaptic Vesicles Syndrome System Therapeutic Agents TorsinA Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Week Yeasts base extracellular mouse model mutant neurochemistry neuron loss neurotransmission neurotransmitter release neurotransmitter uptake novel novel therapeutics promoter protein aggregate research study size uptake yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): DYT1 dystonia is a potentially disabling hyperkinetic movement disorder characterized by sustained or repetitive involuntary muscle contractions and/or abnormal postures. The disorder is caused by a three base pair in-frame deletion in the DYT1 gene resulting in the loss of a glutamic acid residue at position 302/303 in torsinA. In our laboratory we have generated two transgenic mouse models that overexpress human mutant torsinA and develop an abnormal phenotype. The first was generated using a rat neuron-specific enolase promoter and the second a mouse DYT1 promoter (see preliminary data). Interestingly, behavioral alterations develop at approximately 3 weeks, and only 40% of transgenic mice exhibit an abnormal phenotype, a pattern similar to what is seen in human DYT1 dystonia. The basis of why some animals exhibit an abnormal phenotype and others do not is not known. We have shown that dopamine levels are reduced and extracellular glutamate levels are increased in the striatum of transgenic mice. Furthermore, yeast two-hybrid screening identified two important torsinA interacting proteins (TAIP), TAIP1 is implicated in the neurotransmission. Based on the studies performed on our current transgenic model and preliminary data obtained, there is enough evidence suggesting an alteration in neurotransmission, which could underlie the pathophysiology of DYT1 dystonia. In this proposal we will 1) Investigate neurochemical and ultra-structural changes in transgenic mouse models; 2) Investigate the neuroanatomical changes by unbiased stereology to determine the underlying pathology in the two DYT1 transgenic mouse models; 3) Determine the role of TAIP1 in neurotransmission and the effect of torsinA mutation on this function; and 4) Investigate the effect of crossing TAIP1 knockout mice with DYT1 transgenic mice. The long-term goals are to delineate the pathophysiology and develop novel therapeutic agents and ultimately find a cure for this highly debilitating disorder in children. PUBLIC HEALTH RELEVANCE: The purpose of this investigation is to understand the basis of childhood onset dystonia caused by a mutation in DYT1 gene mapped to human chromosome 9. The studies proposed in this application are expected to advance our knowledge of underlying pathophysiology of this syndrome and will lead to development of novel therapies for treatment and possible cure for this highly debilitating condition in affected children.

描述（由申请人提供）：DYT1 肌张力障碍是一种潜在致残性多动性运动障碍，其特征是持续或重复的不自主肌肉收缩和/或异常姿势。该疾病是由 DYT1 基因中的三个碱基对框内缺失引起的，导致 torsinA 中第 302/303 位的谷氨酸残基丢失。在我们的实验室中，我们建立了两种转基因小鼠模型，它们过度表达人类突变体torsinA并产生异常表型。第一个是使用大鼠神经元特异性烯醇化酶启动子生成的，第二个是使用小鼠 DYT1 启动子生成的（参见初步数据）。有趣的是，行为改变在大约 3 周时发生，并且只有 40% 的转基因小鼠表现出异常表型，这种模式类似于人类 DYT1 肌张力障碍中所见的模式。为什么有些动物表现出异常表型而另一些动物则没有，其原因尚不清楚。我们已经证明，转基因小鼠纹状体中的多巴胺水平降低，细胞外谷氨酸水平增加。此外，酵母双杂交筛选鉴定了两种重要的torsinA相互作用蛋白（TAIP），TAIP1与神经传递有关。根据对我们目前的转基因模型进行的研究和获得的初步数据，有足够的证据表明神经传递的改变，这可能是 DYT1 肌张力障碍的病理生理学基础。在本提案中，我们将 1）研究转基因小鼠模型中的神经化学和超微结构变化； 2) 通过公正的体视学研究神经解剖学变化，以确定两种 DYT1 转基因小鼠模型的潜在病理学； 3）确定TAIP1在神经传递中的作用以及torsinA突变对此功能的影响； 4) 研究TAIP1敲除小鼠与DYT1转基因小鼠杂交的效果。长期目标是描述病理生理学并开发新型治疗药物，并最终找到治疗这种高度衰弱的儿童疾病的方法。公共健康相关性：本研究的目的是了解由映射到人类 9 号染色体的 DYT1 基因突变引起的儿童期肌张力障碍的基础。本申请中提出的研究预计将增进我们对该综合征潜在病理生理学的了解，将导致开发新的疗法来治疗和可能治愈受影响儿童的这种高度衰弱的疾病。