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

基本信息

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
项目类别：
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

项目摘要

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.

概括肌张力障碍是一种神经运动障碍，其特征是持续或间歇性肌肉收缩，导致异常运动和姿势的 DYT1 肌张力障碍是一种常染色体显性原发性肌张力障碍。受影响的人患有残疾，并且很多时候只能坐在轮椅上，DYT1 肌张力障碍主要是由这种情况引起的。 DYT1/TOR1A 外显子 5 中的框内 GAG 缺失，导致 C 端区域谷氨酸丢失 torsinA (torsinAΔE) 虽然原发性肌张力障碍传统上被认为是基底神经节起源的疾病，但它是越来越清楚的是，涉及基底神经节和小脑的大脑回路对于同时，我们对torsinA如何发挥作用知之甚少。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：首先，我们开发了一种分子遗传学方法，可以实现这一目标。选择性地针对特定细胞类型的功能，使得一些细胞仍然缺乏torsinA，而另一些细胞我们将使用这种方法来专门针对细胞类型，包括：1）中等多刺神经元，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) 皮质内的谷氨酰胺能神经元，以及 3) 小脑内的浦肯野神经元其次，我们将利用我们的神经元。行为表型和肌电图的经验来表征肌张力障碍相关的缺陷我们将使用肌电图、后肢紧握等方法量化肌肉协同收缩。第三，一项关键的创新是使用先进的高场脑成像。在 11.1 特斯拉时使用体内多壳扩散成像来评估结构退化、静息态功能磁共振成像（fMRI）评估功能连接性，感觉诱发功能磁共振成像（fMRI）评估功能连接在目标 1 中，我们将探索 Tor1a (Dyt1) ΔGAG 的细胞特异性影响。在目标 2 中，我们将探索小鼠模型中的细胞特异性效应。通过 Cre 重组酶表达和 TorsinA 的条件敲除 (cKO) 行为表型的用途。非侵入性神经影像标记物将提供对细胞特异性机制的基本了解与肌张力障碍相关，为未来的小鼠临床前治疗研究提供转化读数，以及这里使用的神经影像标记将直接翻译给人类。