SV2C as a novel mediator of transmitter release and neuroprotection in dopamine cells

SV2C 作为多巴胺细胞递质释放和神经保护的新型介质

基本信息

批准号：
8908284
负责人：
Amy Dunn
金额：
$ 4.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-15 至 2017-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908284
关键词：
1-Methyl-4-phenylpyridinium Address Adult Affect Age Alleles American Animals Basal Ganglia Binding Sites Bradykinesia Brain Calcium Cell Death Cells Chronic Cigarette Clinical Trials Code Corpus striatum structure Cytosol Data Disease Disease Progression Disease model Dopamine Dopaminergic Cell Dorsal Economic Burden Electrochemistry Exocytosis Family Frequencies Functional disorder Genes Genetic Genetic Polymorphism Genotype Glycoproteins Goals Health High Pressure Liquid Chromatography Impaired cognition Incidence Intervention Knock-out Lead Length Mediating Mediator of activation protein Mental Depression Microdialysis Minor Minority Modeling Movement Mus Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Nicotine Onset of illness Parkinson Disease Pathogenesis Pathology Patients Persons Pharmacologic Substance Play Population Promoter Regions Proteins Rest Tremor Risk Rodent Role Scanning Severities Sleep disturbances Smoker Smoking Smoking History Substantia nigra structure Synapses Synaptic Vesicles Therapeutic Toxic effect Ventral Tegmental Area Vesicle base burden of illness cell injury cigarette smoking cigarette smoking disorder risk dopaminergic neuron extracellular gastrointestinal genome wide association study interest member motor deficit motor impairment mouse model neurochemistry neuroprotection new therapeutic target nonhuman primate novel pars compacta prevent protective effect public health relevance pyridine research study smoking cessation synaptotagmin therapeutic target toxicant uptake vesicular monoamine transporter 2

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease affects 1% of adults over the age of 60 and is the second-most common neurodegenerative disease. It is characterized by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta, and clinically, it manifests with severe motor impairments including slowness of movement, bradykinesia, resting tremor, gastrointestinal disruptions, and sleep disturbances. There are currently no treatments to prevent disease onset or curtail disease progression, and identifying potential new targets for pharmaceutical interventions will be imperative to reduce disease incidence and severity. A promising target for PD therapeutics is the dopaminergic vesicle. It has been well-established by our lab and others that impaired vesicular function and capacity for dopamine-for example, as a result of under- expression of the vesicular monoamine transporter 2 (VMAT2)-can lead to progressive dopaminergic degeneration and enhanced vulnerability to dopaminergic toxicants. [Conversely, enhanced vesicular function is neuroprotective]. Our lab is therefore interested in characterizing novel targets of dopamine vesicle function, such as the synaptic vesicle glycoprotein 2C (SV2C). SV2C genotype mediates the protective power of nicotine use, which is the strongest environmental mediator of PD risk. Targeting SV2C may allow us to harness the therapeutic potential of nicotine without exposing patients to negative health consequences associated with nicotine use. We have developed SV2C-KO mice that will allow us to determine this protein's role in mediating dopamine handling and release and its functional interaction with nicotine. Preliminary electrochemistry data suggest that SV2C mediates dopamine vesicular packaging and release, providing further evidence of a potential therapeutic value for targeting SV2C in PD. The goal of this project is to demonstrate that SV2C indeed mediates dopamine handling and release, vulnerability to dopaminergic toxicity by MPTP and neuroprotection by nicotine. Results from this study will show to what extent SV2C plays a role in protecting against pathological dopaminergic degeneration, and it will evaluate its potential as a therapeutic target for PD.

描述（由申请人提供）：帕金森病影响 1% 的 60 岁以上成年人，是第二常见的神经退行性疾病，其特征是黑质致密部的多巴胺能神经元进行性丧失，在临床上，它是一种常见的神经退行性疾病。表现为严重的运动障碍，包括运动缓慢、运动迟缓、静息性震颤破坏、胃肠道紊乱和睡眠障碍，目前尚无治疗方法。预防疾病发作或遏制疾病进展，并确定药物干预的潜在新靶点对于降低疾病发生率和严重程度至关重要。我们的实验室和其他人已经确定，多巴胺能囊泡是帕金森病治疗的一个有希望的靶点。囊泡功能和多巴胺能力受损，例如，由于囊泡单胺转运蛋白 2 (VMAT2) 表达不足，可导致进行性多巴胺能变性，并增加对多巴胺的脆弱性。 [相反，增强的囊泡功能具有神经保护作用]。因此，我们的实验室对表征多巴胺囊泡功能的新靶点感兴趣，例如突触囊泡糖蛋白 2C (SV2C) 基因型介导尼古丁使用的保护作用。以 SV2C 为目标的 PD 风险最强的环境介质可能使我们能够利用尼古丁的治疗潜力，而不会使患者面临负面健康。我们开发了 SV2C-KO 小鼠，这将使我们能够确定该蛋白质在介导多巴胺处理和释放中的作用及其与尼古丁的功能相互作用。初步电化学数据表明 SV2C 介导多巴胺囊泡包装和释放，从而提供进一步的信息。靶向 SV2C 在 PD 中具有潜在治疗价值的证据该项目的目标是证明 SV2C 确实介导多巴胺的处理和释放，以及对多巴胺的脆弱性。 MPTP 的多巴胺能毒性和尼古丁的神经保护作用本研究的结果将显示 SV2C 在防止病理性多巴胺能变性方面发挥的作用，并将评估其作为 PD 治疗靶点的潜力。