Novel Molecular Genetic Approaches for the Prevention and Treatment of Parkinsons

预防和治疗帕金森病的新分子遗传学方法

基本信息

批准号：
8773471
负责人：
Thomas Hnasko
金额：
$ 19.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773471
关键词：
Accounting Address Animal Model Basal Ganglia Behavior Behavioral Biochemical Bradykinesia Cell Death Cells Cessation of life Corpus striatum structure Cytoplasm Data Dopamine Dopamine D2 Receptor Electron Microscopy Electrophysiology (science)Excitatory Synapse Gene Expression Globus Pallidus Glutamate Transporter Glutamates Goals Human Knock-out Knockout Mice Lead Lesion MPTP Poisoning Measurement Medial Midbrain structure Modeling Molecular Genetics Molecular Target Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Nucleus Accumbens Output Parkinson Disease Pathway interactions Population Prevention Prevention approach Protein Isoforms Proteins Resistance Rest Tremor Slice Structure of subthalamic nucleus Substantia nigra structure Symptoms Synaptic Transmission Synaptic Vesicles Testing Therapeutic Toxic effect Ventral Tegmental Area Viral Viral Vector Work base cytotoxic dopaminergic neuron gamma-Aminobutyric Acid in vivo insight mature animal motor disorder mouse model neural circuit neuroprotection neurotransmitter release novel novel strategies optogenetics pH gradient postsynaptic presynaptic prevent progressive neurodegeneration public health relevance research study response selective expression uptake vesicular glutamate transporter 1 vesicular glutamate transporter 2 vesicular monoamine transporter

项目摘要

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a motor disorder brought on by neurodegeneration of midbrain dopamine neurons. However, a subpopulation of these cells is relatively spared both in PD and in PD animal models - those that project from the medial ventral tegmental area (VTA) to the ventromedial striatum (VMS or the medial shell of the nucleus accumbens). This projection also contains many dopamine neurons that express the vesicular glutamate transporter (VGLUT2) and co-release the excitatory neurotransmitter glutamate. Because VGLUT2 and the vesicular monoamine transporter (VMAT2) appear to localize to an overlapping population of synaptic vesicles in the VMS, the vesicular co-entry of glutamate may confer neuroprotection by increasing the vesicular pH gradient (DpH). Larger DpH would then be predicted to increase the vesicular storage of dopamine, serving to sequester dopamine and other potentially cytotoxic VMAT2 substrates into vesicular bodies where their toxicity is mitigated. The first aim of this proposal will test whether VGLUT2 confers neuroprotective benefits in an MPTP lesion model of PD using selective conditional knockout mice and viral expression strategies. Following the loss of dopamine neurons in PD or PD lesion models, output from the dopaminoceptive medium spiny neurons (MSN) in the basal ganglia is dysregulated. In particular, over-activation of the dopamine D2 receptor containing MSNs of the indirect pathway and consequent over-excitation of the subthalamic nucleus appear to account for the most severe motor symptoms associated with PD. We will thus test whether flipping the polarity of indirect pathway output from inhibitory to excitatory can restore motor behaviors in a PD lesion model. These studies will test novel hypotheses and a new molecular target (VGLUT2) in the neural circuitry that contribute to PD. The work will provide important information about the plasticity of these circuits to changes in excitatory transmitter release, an may lead to new approaches for the treatment and prevention of Parkinson's Disease.

描述（由申请人提供）：帕金森氏病（PD）是中脑多巴胺神经元神经变性引起的运动障碍。然而，这些细胞的亚群在PD和PD动物模型中相对宽容，PD动物模型是从内侧腹侧侧距区域（VTA）到腹侧纹状体（VMS或Occumbens核的内侧壳）的。该投影还包含许多表达囊泡谷氨酸转运蛋白（VGLUT2）的多巴胺神经元，并共释放兴奋性神经递质谷氨酸。由于VGLUT2和囊泡单胺转运蛋白（VMAT2）似乎定位于VMS中的突触囊泡重叠的种群，因此谷氨酸的囊泡合作可能通过增加囊泡pH梯度（DPH）来赋予神经保护作用。然后，将预测较大的DPH会增加多巴胺的囊泡储存，从而将多巴胺和其他潜在的细胞毒性VMAT2底物隔离到降低其毒性的囊泡体中。该提案的第一个目的是测试VGLUT2是否使用选择性条件基因敲除小鼠和病毒表达策略在PD的MPTP病变模型中是否赋予神经保护作用。在PD或PD病变模型中多巴胺神经元丧失之后，基底神经节中多巴胺感受培养基神经元（MSN）的输出失调。特别是，多巴胺D2受体的过度激活含有间接途径的MSN，因此过度激活丘脑核核似乎是与PD相关的最严重的运动症状。因此，我们将测试将间接途径从抑制性兴奋性转移到兴奋性的极性是否可以恢复PD病变模型中的运动行为。这些研究将测试新的假设和有助于PD的神经回路中的新分子靶标（VGLUT2）。这项工作将提供有关这些电路对兴奋性发射器释放变化的可塑性的重要信息，这可能会导致新的治疗和预防帕金森氏病的方法。