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Oxidative Stress and Glutamate Excitotoxicity on Aged Dopaminergic Neruons

氧化应激和谷氨酸对老年多巴胺能神经元的兴奋毒性

基本信息

批准号：
8531105
负责人：
HEATHER A BOGER
金额：
$ 21.34万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531105
关键词：
Acute Address Age Age-Months Aging Agonist Area Award Basal Ganglia Bicuculline Brain CREB1 gene Chronic Corpus striatum structure Doctor of Philosophy Dopamine Dopamine D2 Receptor Electrochemistry Functional disorder Future GLAST Protein Gene Deletion Genetic Glutamate Transporter Glutamates Goals Grant Kentucky Laboratories Learning Life Link Mentors Microspheres Molecular Biology Motor Motor Activity Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences Oxidative Stress PTGS1 gene PTGS2 gene Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Phase Production Raclopride Request for Proposals Research Research Project Grants Research Proposals Resolution Reverse Transcriptase Polymerase Chain Reaction Signaling Molecule Structure of subthalamic nucleus Substantia nigra structure System Techniques Time Toxic effect Training Universities Up-Regulation Western Blotting age related aged awake career catalase dopaminergic neuron early onset excitotoxicity gamma-Aminobutyric Acid glial cell line derived neurotrophic factor, mouse glial cell-line derived neurotrophic factor glutathione peroxidase in vivo insight motor impairment mouse model nanoparticle neurotransmission novel presynaptic public health relevance receptor expression receptor sensitivity response ropinirole skills statistics therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): This proposal requests support for a comprehensive training plan that will enable Heather Boger, PhD, to broaden, enhance, and refine her technical skills that are necessary for a productive independent research career. Dr. Boger will receive multifaceted training during the mentored phase (Year 1-2) of the award from a team of collaborating mentors that include training in molecular biology, electrochemistry, production of nanoparticles (microspheres), and statistics. The research plan that is proposed during the independent phase (Year 3-5) builds on this training and focuses more specifically on mechanisms involved with neurodegeneration. Aging and Parkinson's disease (PD), a known neurodegenerative disease resulting in motor impairments, has been associated with a reduction of glial cell line-derived neurotrophic factor (GDNF) in the substantia nigra, increased oxidative stress, and an increase in the indirect pathway of the basal ganglia circuitry (including increase dopamine D2 receptor expression, increased nigral glutamate release from overactive subthalamic nucleus neurons, and decreased nigrostriatal dopamine expression and function). We have demonstrated that a mouse model with a genetic reduction of GDNF have early-onset motor dysfunction and evidence of increased indirect pathway function, such as increased striatal D2 receptor expression and accelerated decline in nigrostriatal expression. However, it is not known whether a partial gene deletion of GDNF impacts subthalamic nucleus glutamate release into the substantia nigra and oxidative stress with age. Therefore, the overall hypothesis of this research proposal is that the intrinsic GDNF loss enhances nigrostriatal DAergic system dysfunction by increasing STN-nigral glutamate excitotoxicity via oxidative stress. To address this hypothesis, three specific aims have been formulated: Aim 1) The neuronal response to acute administration of GDNF is altered in mice with a genetic reduction of GDNF, Aim 2) Chronic administration of GDNF will alleviate the age-related effects of a partial loss of GDNF on DA function, and Aim 3) The progress DAergic loss due to less availability of GDNF dysregulates the glutamatergic input from the subthalamic nucleus in the substantia nigra, resulting in elevated oxidative stress and continued DAergic dysfunction. Findings from these studies will provide insight into the mechanisms underlying early-onset dopaminergic loss associated with a partial loss of GDNF and may identify therapeutic targets to reduce oxidative stress, nigrostriatal dopamine loss, and motor dysfunction occurring with aging and parkinsonism. In addition, results from these studies will serve to guide Dr. Boger's future independent research in the area of systems neuroscience. PUBLIC HEALTH RELEVANCE: Glial cell line-derived neurotrophic factor (GDNF) is reduced in Parkinson's disease patients and we have shown that mice with a partial loss of GDNF have accelerated age-related loss of motor function and nigrostriatal dopamine, but the relationship between GDNF reductions and dopamine loss is unknown. We propose that the dopamine loss as a result of long-term reduction of GDNF results in increased glutamate release from the subthalamic nucleus into the substantia nigra resulting in oxidative stress and continued dopaminergic damage. Furthermore, exogenous GDNF administration will alleviate the dopaminergic damage associated with increased glutamate toxicity as a result of a life-long reduction of GDNF.

描述（由申请人提供）：本提案要求支持一个全面的培训计划，使石楠博格博士，以扩大，增强和完善她的技术技能，是必要的生产独立的研究生涯。博格博士将在该奖项的指导阶段（1-2年）接受来自合作导师团队的多方面培训，包括分子生物学，电化学，纳米颗粒（微球）生产和统计学方面的培训。在独立阶段（3-5年）提出的研究计划建立在这种培训的基础上，更具体地关注与神经退行性变有关的机制。帕金森病（Parkinson's disease，PD）是一种已知的导致运动障碍的神经退行性疾病，与黑质中胶质细胞源性神经营养因子（glial cell line-derived neurotrophic factor，GDNF）的减少、氧化应激的增加以及基底神经节回路间接途径的增加有关（包括增加多巴胺D2受体表达，增加过度活跃的丘脑底核神经元的黑质谷氨酸释放，以及黑质纹状体多巴胺表达和功能降低）。我们已经证明，GDNF基因减少的小鼠模型具有早发性运动功能障碍和间接途径功能增加的证据，例如纹状体D2受体表达增加和黑质纹状体表达加速下降。然而，GDNF的部分基因缺失是否会影响丘脑底核谷氨酸释放到黑质和氧化应激随年龄的增长，目前尚不清楚。因此，本研究建议的总体假设是，内源性GDNF丢失通过氧化应激增加STN-黑质谷氨酸兴奋性毒性来增强黑质纹状体DA能系统功能障碍。为了解决这一假设，制定了三个具体目标：目的1）在GDNF基因减少的小鼠中，对GDNF急性给药的神经元反应发生改变，目的2）GDNF慢性给药将减轻GDNF部分丧失对DA功能的年龄相关影响，和目的3）由于GDNF可用性减少而导致DA能损失的进展使黑质中丘脑底核的谷氨酸能输入失调，导致氧化应激升高和持续DA能功能障碍。这些研究的结果将提供深入了解与GDNF部分丧失相关的早发性多巴胺能丧失的机制，并可能确定治疗靶点，以减少氧化应激，黑质纹状体多巴胺丧失和衰老和帕金森综合征发生的运动功能障碍。此外，这些研究的结果将指导博格博士未来在系统神经科学领域的独立研究。公共卫生关系：胶质细胞源性神经营养因子（GDNF）在帕金森病患者中减少，我们已经表明GDNF部分缺失的小鼠具有加速的与年龄相关的运动功能和黑质纹状体多巴胺的丧失，但GDNF减少和多巴胺丧失之间的关系尚不清楚。我们认为，由于GDNF的长期减少导致多巴胺损失，导致从丘脑底核到黑质的谷氨酸释放增加，从而导致氧化应激和持续的多巴胺能损伤。此外，外源性GDNF给药将减轻与由于GDNF的终身减少而增加的谷氨酸毒性相关的多巴胺能损伤。