The Effects of Traumatic Brain Injury in Alpha Synuclein and Dopamine Regulation

创伤性脑损伤对α突触核蛋白和多巴胺调节的影响

基本信息

批准号：
7803996
负责人：
Samuel Shin
金额：
$ 4.64万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7803996
关键词：
Accounting Acute Affect Aldehydes Amino Acids Attenuated Behavioral Brain Carboxy-Lyases Cause of Death Chronic Cognitive deficits Corpus striatum structure Critiques Development Disinhibition Dopamine Dopamine Agonists Enzymes Functional disorder Future High Pressure Liquid Chromatography Homeostasis Human Hydrogen Peroxide Hypothalamic structure Immunohistochemistry Incidence Individual Injury Knock-out Knockout Mice Lead Link Literature Measures Mediating Metabolism Microdialysis Monoamine Oxidase Inhibitors Mus Neurodegenerative Disorders Neurons Neurotransmitters Outcome Oxidative Stress Pathologic Pathology Permeability Proteins Rattus Regulation Risk Role System Testing Therapeutic Therapeutic Agents Time Tissues Traumatic Brain Injury Tyrosine 3-Monooxygenase Tyrosine Hydroxylase Inhibitor United States Update Vesicle Western Blotting Wild Type Mouse alpha synuclein base brain tissue cognitive function disability dopamine transporter dopaminergic neuron enzyme activity frontal lobe improved in vivo insight meetings neurotoxic neurotransmission prevent research study reuptake synuclein therapeutic development uptake

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) occurs in the United States at an incidence of 200 per 100,000 people annually, causing long lasting functional and cognitive deficits due to disruptions of various neurotransmitter systems, including dopamine (DA). Based on our past studies and findings in the literature, TBI may induce both DA increase in neurons and aggregation of a-synuclein (AS). AS aggregation can induce dysregulation of DA synthesis and reuptake leading to excess DA intracellularly, and intracellular DA excess can lead to AS aggregation. It is clear from these evidences that DA and AS regulation may be interrelated. Clarifying the link between AS pathology and DA dysfunction will improve our understanding of the mechanism of cognitive deficits following TBI and contribute to development of therapeutic strategies to prevent and minimize DA neurotransmission deficits. Furthermore, it may provide us with an insight into how TBI may lead to future risk of neurodegenerative diseases like synucleinopathies. We hypothesize that the acute DA increase after TBI may be a significant contributor to AS aggregation, and this aggregation of AS may furthermore contribute to dysregulation of DA. To support this hypothesis. Specific Aim 1 will examine the effect of inhibiting DA synthesis or metabolism pharmacologically to prevent AS aggregation due to acute tissue DA increase after TBI. Western blotting and immunohistochemistry will be performed to confirm aggregation of AS. Specific Aim 2 will examine the effect of AS aggregates on DA regulation by comparing the differences between wild type and AS knockout mice in the levels and activities of enzymes regulating DA as well as level and release of DA itself. Enzyme levels will be measured by Western blots and enzyme activities will be assessed by measuring the products by high performance liquid chromatography. High performance liquid chromatography and microdialysis in vivo will be used to confirm the levels and release of DA. This project investigates how the loss of regulation of neurotransmitter dopamine occurring after TBI may be due to the affects of pathological changes in a-synuclein protein. Understanding this mechanism will help us develop therapeutic strategies to treat functional deficits after TBI and possible future development of neurodegenerative diseases. NOTE: The critiques of individual reviewers are provided below in an essentially unedited form. These critiques were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

描述（由申请人提供）：创伤性脑损伤（TBI）每年以每100,000人200人的发病率发生，由于多巴胺（DA）在内的各种神经递质系统的破坏，导致了持久的功能和认知缺陷。基于我们过去的研究和文献发现，TBI可能会诱导神经元的增加和A-突触核蛋白的聚集（AS）。由于聚集会诱导DA合成和再摄取失调，导致细胞内过多，细胞内DA过量会导致聚集。从这些证据中可以明显看出，DA和法规可能相互关联。阐明AS病理与DA功能障碍之间的联系将提高我们对TBI后认知缺陷机制的理解，并有助于开发治疗策略，以预防和最大程度地减少DA神经传递缺陷。此外，它可能使我们能够了解TBI如何导致诸如突触核苷酸病（如突触核断裂病）的未来风险。我们假设TBI后的急性DA增加可能是AS聚集的重要贡献，并且AS的这种聚集可能会导致DA的失调。支持这一假设。具体目标1将检查抑制DA合成或药理代谢的效果，以防止TBI后急性组织DA引起的聚集。将进行蛋白质印迹和免疫组织化学，以确认AS的聚集。特定的目标2将通过比较调节DA的酶的水平和活性以及DA本身的水平和释放的酶的水平和活动中的野生类型和敲除小鼠之间的差异来检查AS AS对DA调节的影响。酶水平将通过蛋白质印迹测量，酶活性将通过高性能液相色谱测量产物来评估。高性能液相色谱和体内微透析将用于确认DA的水平和释放。该项目研究了TBI后发生的神经递质多巴胺的调节损失可能是由于A-核蛋白蛋白质中病理变化的影响。了解这种机制将有助于我们制定治疗策略，以治疗TBI之后的功能缺陷以及神经退行性疾病的未来发展。注意：以下基本未经编辑的形式提供了个人审阅者的批评。这些批评是在审查会议之前准备的，可能在会议上讨论后未经更新或修订。因此，他们可能无法在小组讨论的结束或小组的最终多数意见中完全反映单个审稿人的最终意见。上面的讨论简历和摘要总结了小组讨论的最终结果。