Molecular etiology of early onset dystonia

 描述（由申请人提供）：（总体摘要）肌张力障碍是第三常见的运动障碍，大多数病例具有遗传倾向。我们的总体目标是阐明遗传性早发性脑梗死的分子、细胞和神经元回路缺陷 肌张力障碍，并找到共同的途径，其病因和潜在的靶向药物的治疗干预。我们的团队成员发现了三个潜在的早发性肌张力障碍基因，TOR 1A（DYT 1），THAP 1（DYT 6）和GNAL（DYT 25），并开发和表征了DYT 1肌张力障碍的小鼠和果蝇模型，以及启动对DYT 6和DYT 25肌张力障碍小鼠模型的研究。我们假设，核心病理生理学在于异常的神经递质信号传导，主要是在纹状体，这表现在整个生命的异常突触可塑性。研究将分析神经元文化，以及神经生理学在这些肌张力障碍小鼠模型，以及增强/抑制基因在果蝇突变体。共同的主题包括纹状体中胆碱能和多巴胺能神经递质的相互作用，信号蛋白的转录和功能控制，以及核糖核蛋白颗粒（RNP）中mRNA在突触翻译中的转运。我们将接近这些主题的研究工具，包括国家的最先进的人类分子遗传学，原代神经元和iPS细胞衍生的神经元培养，和果蝇和小鼠模型的肌张力障碍检查使用遗传和细胞生物学方法和电生理分析切片外植体和微透析小鼠模型。这个高度整合的P01将由Xandra Breakefield博士，主任和劳里Ozelius，联合主任领导，包括：项目1 -“原发性扭转肌张力障碍的基因和易感因素”（PI博士劳里Ozelius，山。Sinai Sch. Med.）;项目2 -“扭转蛋白A作为受体介导的信号传导的关键环节”（PI博士Xandra Breakefield，Co-Is博士D。Cristopher Bragg和Naoto Ito，马萨诸塞州Gen. Hosp.）;项目3 -“肌张力障碍小鼠模型中的胆碱能和多巴胺能机制”（大卫·斯坦德特博士，阿拉巴马大学）。Birmingham）;核心A -管理;和核心B -临床核心（Nutan Sharma博士，Mass. Gen. Hosp.）。临床信息和样本直接输入项目1、2和3。这些研究将阐明参与人类肌张力障碍的常见分子途径，以告知治疗进展。

 DESCRIPTION (provided by applicant): (Overall Abstract) Dystonia is the third most common movement disorder with most cases having a hereditary predisposition. Our overall goal is to elucidate the molecular, cellular and neuronal circuitry defects in hereditary forms of early onset dystonia and to find common pathways in their etiology and potential targeted drugs for therapeutic intervention. Members of our team discovered three genes underlying early onset dystonia, TOR1A (DYT1), THAP1 (DYT6) and GNAL (DYT25) and have developed and characterized mouse and Drosophila models of DYT1 dystonia, as well as initiating studies on mouse models of DYT6 and DYT25 dystonia. We hypothesize that the core pathophysiology lies in abnormal neurotransmitter signaling, primarily in the striatum, which manifests throughout life as abnormal synaptic plasticity. Studies will analyze neuronal cultures, as well as neurophysiology in these dystonia mouse models, as well as enhancer/suppressor genes in Drosophila mutants. Common themes include cholinergic and dopaminergic neurotransmitter interactions in the striatum, transcriptional and functional control of signaling proteins, and transport of mRNAs in ribonucleoprotein particles (RNPs) for translation at synapses. We will approach these themes with an armamentarium of research tools, including state-of-the-art human molecular genetics, primary neuronal and iPS cell-derived neuronal cultures, and Drosophila and mouse models of dystonia examined using genetic and cell biologic methods and electrophysiologic analysis of slice explants and microdialysis in mouse models. This highly integrated P01 will be led by Dr. Xandra Breakefield, Director and Laurie Ozelius, Co-Director and includes: Project 1 - "Genes and susceptibility factors in primary torsion dystonia" (PI Dr. Laurie Ozelius, Mt. Sinai Sch. Med.); Project 2 - "TorsinA as a key link in receptor-mediated signaling" (PI Dr. Xandra Breakefield, Co-Is Drs. D. Cristopher Bragg and Naoto Ito, Mass. Gen. Hosp.); Project 3 - "Cholinergic and dopaminergic mechanisms in mouse models of dystonia" (Dr. David Standaert, Univ. Ala. Birmingham); Core A - Administration; and Core B - Clinical Core (Dr. Nutan Sharma, Mass. Gen. Hosp.). Clinical information and samples feed directly into Projects 1, 2 and 3. These studies will elucidate common molecular pathways involved in human dystonia to inform therapeutic advances.