权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of Striatal Cholinergic Interneurons in Dystonia

纹状体胆碱能中间神经元在肌张力障碍中的作用

基本信息

批准号：
10343290
负责人：
Scott Allen Norris
金额：
$ 62.78万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343290
关键词：
Address Adult Adult-Onset Dystonias Affect Age Analysis of Variance Animal Model Binding Biochemical Blepharospasm Body Regions Brain Brain region Cerebellum Cervical Characteristics Cholinergic Receptors Clinical Control Groups Corpus striatum structure Data Development Disease Dopamine Drug Targeting Dystonia Employment Status Focal Dystonias Functional Magnetic Resonance Imaging Functional disorder Future Genotype Goals Heterogeneity Human Interneuron function Interneurons Knowledge Larynx Lead Limb Dystonia Magnetic Resonance Imaging Measurement Measures Mediating Methods Mission Modeling Molecular Multimodal Imaging Muscle Neurons Neurotransmitters Participant Pathogenicity Pathway interactions Persons Pharmaceutical Preparations Phenotype Play Positron-Emission Tomography Public Health Quality of life Research Research Personnel Research Priority Rest Role Seeds Severities Signal Transduction Subgroup System Testing Thalamic structure Therapeutic Intervention Translating United States National Institutes of Health Upper Extremity acetylcholine transporter cholinergic comparison group disability effective therapy gene discovery improved in vivo innovation interest motor control network dysfunction neuroimaging neuroimaging marker new therapeutic target novel presynaptic radioligand regional difference sex therapeutic target uptake

项目摘要

PROJECT SUMMARY There is a fundamental gap in understanding the pathophysiology of isolated adult-onset dystonia due to genotypic and phenotypic heterogeneity. Determining common pathophysiologic mechanisms across dystonia subtypes is a critical step toward developing more generalizable and effective therapies. Emerging evidence points to striatal cholinergic interneurons (ChIs) playing a key role in the pathophysiology of dystonia, including biochemical and network-level dysfunction. In addition to offering a common therapeutic target, our findings are likely to benefit gene discovery and research on other disabling, less common forms of dystonia. Over the long term, results could guide researchers to perform greater in depth histopathological and biochemical studies in the brain that can lead to identification of new targets for therapeutic intervention. Our goal is to apply a recently developed PET radioligand, [18F]VAT, which possesses high selectivity for vesicular acetylcholine transporters, to investigate striatal ChIs. Structural and resting state functional MRI will examine the relationship of striatal ChIs to related brain networks across different focal dystonia subtypes. Identification of network-level changes across dystonia subtypes will provide better understanding of common pathophysiology and could potentially provide means to assess target engagement for future therapeutic interventions. The central hypothesis is that striatal ChIs contribute to a common pathophysiological mechanism in humans with isolated adult-onset focal dystonia, and that cholinergic integrity relates to striatal functional connectivity and clinical features of dystonia. The rationale for the proposed research is the likely involvement of striatal ChIs in a) normal motor control and b) animal models of dystonia. ChIs are autonomously active and mediate a baseline presynaptic inhibitory tone on striatal medium spiny neurons against the excitatory cortical drive, likely via modulation of dopamine release via presynaptic cholinergic receptors on nigrostriatal dopaminergic terminals. They also receive input from intralaminar thalamic neurons innervated by cerebellar afferents, that when dysfunctional may contribute to dystonic phenotypes. Thus, ChIs may contribute to a common pathogenic mechanism involving cortico-striata-thalamic or cerebello-thalamo-striatal networks. This hypothesis will be tested by pursuing three specific aims: Determine if 1) dysfunction of striatal ChIs is a common mechanism across isolated dystonia subtypes; 2) common aberrations in functional striatal brain networks underlie the isolated dystonia subtypes; 3) clinical characteristics relate to markers of ChIs and brain network dysfunction across different isolated adult-onset focal dystonias. This approach is innovative as it uses comprehensive multimodal imaging to investigate novel PET- measured cholinergic integrity and related functional networks. The proposed research is significant because it is expected to critically advance the understanding of dystonia. Ultimately, such knowledge may provide critical rationale to identify and test new therapeutic targets and better understand other disabling forms of dystonia.

项目总结