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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.

总结