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：
9790979
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/9790979
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 Knock-out 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 cell type cholinergic cholinergic neuron 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 aggregate 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，这会导致异常运动和姿势。受影响的人被残疾，很多时候限于轮椅。 dyt1/tor1a的外显子5中的An-Frame插科打删除，导致C末端区域的谷氨酸损失 Torsina（TorsinaΔE）。很明显，涉及基底神经节和小脑的大脑电路是促进肌张力障碍的症状。特定的细胞类型以及特定的大脑区域将无人机运动缺陷和病理生理特征签名在解决这个问题的问题上，我们将利用我们的实验团队的三个关键创新定位我们的小组以实现这一目标。有选择地靶向特定细胞类型的功能，以便在托西娜（Torsina 正常功能。我们将使用此apporo专门针对细胞类型，包括：1）胆碱能神经元，多巴胺受体2神经元和基底神经节内多巴胺能神经元，2）皮质中的谷氨酰胺能神经元，以及3）小脑中的purkinje神经元。具有行为表型和肌电图的经验，表征了脚趾中肌张力障碍相关的缺陷小鼠模型。我们将使用肌电图，后肢和其他与肌张力障碍相关的运动缺陷的测试。在11.1 Tesla时，使用体内多壳扩散成像来评估结构变性，静止状态功能磁共振成像（fMRI）评估功能连接器和感官evk的fMRI以评估您跨大脑1的感觉神经元的完整性1，在AIM 1中，我们将探索tor1a（dyt1）Δgag上的细胞体系 AIM 2中的杂合敲入（Ki）小鼠。通过Torsina的Cre-Recombinase表达敲除（CKO）。和非侵入性神经影像学标记将提供对细胞特异性机制的基本理解与肌张力障碍有关，为小鼠的未来临床前治疗研究提供翻译读数，并为这里使用的神经影像标记将直接转化为人类。