Non-Invasive Markers of Neurodegeneration in Movement Disorders

运动障碍神经退行性变的非侵入性标志物

• 批准号: 10242723
• 负责人: YUQING LI
• 金额: $ 41.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242723
• 关键词: Address; Affect; Afferent Neurons; Basal Ganglia; Basal Ganglia Diseases; Behavioral; Brain; Brain imaging; Brain region; C-terminal; CRISPR/Cas technology; Cells; Cerebellum; Corpus striatum structure; Diffusion; Disabled Persons; Dopamine Receptor; Dyskinetic syndrome; Dystonia; Electromyography; Enterobacteria phage P1 Cre recombinase; Exons; Functional Magnetic Resonance Imaging; Functional disorder; Future; GAG Gene; Genes; Genetic; Glutamic Acid; Goals; Grant; Hindlimb; Human; Image; Interneurons; Knock-in; Knock-in Mouse; Knockout Mice; Link; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Motor; Movement Disorders; Mus; Muscle; Muscle Contraction; Nerve Degeneration; Neurologic; Neurons; Pathway interactions; Pharmacology; Phenotype; Positioning Attribute; Posture; Primary Dystonias; Prosencephalon; Proteins; Purkinje Cells; Rest; Sensory; Specificity; Structure; Symptoms; System; TOR1A gene; Testing; Therapeutic; Therapeutic Studies; Time; TorsinA; Wheelchairs; base; behavioral phenotyping; cell type; cholinergic; cholinergic neuron; conditional knockout; dopaminergic neuron; experience; experimental study; genetic approach; in vivo; innovation; misfolded protein; motor deficit; mouse model; neuroimaging; neuroimaging marker; novel; phenotypic biomarker; pre-clinical; protein aggregation; protein folding; receptor; translation to humans

SUMMARY Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, which result in abnormal movements and postures. DYT1 dystonia is an autosomal dominant primary dystonia. Affected individuals are disabled and many times confined to a wheelchair. DYT1 dystonia results primarily from an in-frame GAG deletion in exon 5 of DYT1/TOR1A, resulting in a loss of glutamic acid at the C-terminal region of torsinA (torsinAΔE). Although primary dystonia is classically considered a disorder of basal ganglia origin, it is becoming clear that brain circuits that involve both the basal ganglia and cerebellum are fundamental in contributing to the symptoms of dystonia. At the same time, we know very little about how torsinA function in specific cell types and across specific brain regions will unleash motor deficits and pathophysiological signatures of dystonia. To address this question, we will leverage three key innovations from our experimental team that position our group to accomplish this goal. First, we have developed a molecular genetics approach that can selectively target the function of specific cell types, such that some cells remain deficient in torsinA while others function normally. We will use this approach to specifically target cell types including: 1) medium spiny neurons, cholinergic neurons, dopamine receptor 2 neurons, and dopaminergic neurons within basal ganglia, 2) glutaminergic neurons within cortex, and 3) Purkinje neurons within cerebellum. Second, we will leverage our experience in behavioral phenotyping and electromyography to characterize dystonia-related deficits in the mouse models. We will quantify muscle co-contraction using electromyography, hindlimb clasping, and other tests of dystonia-related motor deficits. Third, a key innovation will be to use advanced, high-field brain imaging at 11.1 Tesla using in vivo multi-shell diffusion imaging to assess structural degeneration, resting state functional magnetic resonance imaging (fMRI) to assess functional connectivity, and sensory-evoked fMRI to assess the integrity of sensory neurons across the brain. In Aim 1, we will explore cell-specific effects on Tor1a (Dyt1) ΔGAG heterozygous knock-in (KI) mice. In Aim 2 we will explore cell-specific effects in a mouse model characterized by Cre-recombinase expression and conditional knock-out (cKO) of torsinA. The use of behavioral phenotypes and non-invasive neuroimaging markers will provide fundamental understanding of the cell-specific mechanisms related to dystonia, provide translational read-outs for future preclinical therapeutic studies in mouse, and the neuroimaging markers used here will have direct translation to humans.

总结 肌张力障碍是一种以持续或间歇性肌肉收缩为特征的神经运动障碍， 这会导致不正常的动作和姿势。DYT 1肌张力障碍是一种常染色体显性遗传的原发性肌张力障碍。 受影响的人是残疾人，许多时候只能坐轮椅。DYT 1肌张力障碍主要由 DYT 1/TOR 1A外显子5中的符合读码框的GAG缺失，导致C-末端区域的谷氨酸缺失 TorsinA（TorsinAΔE）。虽然原发性肌张力障碍通常被认为是基底神经节起源的疾病，但它是一种神经系统疾病。 越来越清楚的是，涉及基底神经节和小脑的大脑回路是基础， 导致肌张力障碍的症状与此同时，我们对torsinA在 特定的细胞类型和特定的大脑区域将释放运动缺陷和病理生理特征 肌张力障碍为了解决这个问题，我们将利用我们实验团队的三项关键创新， 让我们的团队实现这一目标。首先，我们开发了一种分子遗传学方法， 选择性地靶向特定细胞类型的功能，使得一些细胞仍然缺乏扭转蛋白A，而另一些细胞仍然缺乏扭转蛋白A。 功能正常。我们将使用这种方法来专门靶向细胞类型，包括：1）中型棘神经元， 基底神经节内的胆碱能神经元、多巴胺受体2神经元和多巴胺能神经元，2） 皮质内的多巴胺能神经元; 3）小脑内的浦肯野神经元。第二，我们将利用我们的 在行为表型和肌电图方面的经验，以表征肌张力障碍相关的缺陷， 小鼠模型。我们将使用肌电图、后肢紧握和其他方法来量化肌肉的共同收缩。 肌张力障碍相关的运动缺陷的测试。第三，一个关键的创新将是使用先进的高场脑成像技术 在11.1特斯拉下，使用体内多壳层扩散成像评估结构变性、静息状态功能 磁共振成像（fMRI）评估功能连接，感觉诱发的fMRI评估 感觉神经元的完整性。在目的1中，我们将探索细胞特异性对Tor 1a（Dyt 1）ΔGAG的影响 杂合基因敲入（KI）小鼠。在目标2中，我们将在小鼠模型中探索细胞特异性效应， 通过Cre重组酶表达和扭转蛋白A的条件性敲除（cKO）。行为表型的使用 非侵入性神经影像学标记物将提供对细胞特异性机制的基本理解 与肌张力障碍相关，为未来的小鼠临床前治疗研究提供翻译读数， 这里使用的神经成像标记将直接翻译给人类。