Methamphetamine, Stress and Brain Endothelium

甲基苯丙胺、压力和脑内皮细胞

基本信息

批准号：
8599015
负责人：
Bryan K Yamamoto
金额：
$ 46.53万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599015
关键词：
Acute Address Bacteria Bacterial Infections Benchmarking Biological Blood Blood - brain barrier anatomy Blood capillaries Brain Brain Injuries Cerebrum Chronic stress Comorbidity Diffusion Dinoprostone Disease Dose Drug Exposure Drug abuse Elements Endothelium Event Exposure to Extravasation Future Goals Health Human Hyperthermia Infiltration Inflammation Inflammatory International Measures Mediating Methamphetamine Mission Modeling Neurobiology Neurologic Neurotransmitters Oral Oral cavity Overdose Permeability Pharmaceutical Preparations Phosphorylation Phosphotransferases Porphyromonas gingivalis Post-Traumatic Stress Disorders Prostaglandin-Endoperoxide Synthase Proteins Public Health Rattus Regimen Rho-associated kinase Risk Role Seizures Self Administration Self-Administered Signal Transduction Stress Stroke Structure System Testing Therapeutic Tight Junctions Time Toxic effect Toxin Traumatic Brain Injury Work base capillary design fluorescein isothiocyanate dextran innovation methamphetamine abuse methamphetamine exposure neuroinflammation neurotoxic neurotoxicity novel oral bacteria prophylactic prostanoid receptor EP1 public health relevance relating to nervous system success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The rampant abuse of methamphetamine (Meth) and its documented toxicity to brain neurotransmitter systems are well known but its potential damage to other targets such as the brain microvascular endothelium has been overlooked. Moreover, because Meth is highly co-morbid with other health concerns such as stress and post-traumatic stress disorder, it is imperative that the mechanistic underpinnings between stress and Meth are understood so that effective therapeutic strategies can be developed to effectively treat the scope of Meth abuse and overdose. The proposal examines a new consequence associated with the co-morbidity of stress and Meth abuse that is evidenced by long-term damage to the blood-brain barrier (BBB) and brain microvascular endothelium. The long term goal is to identify the comprehensive effects associated with this co-morbidity and assess the risk to human health produced by stress-induced augmentation of brain injury resulting from the abuse of Meth. Our working model provides the basis for the hypothesis that chronic stress-induced neuroinflammation is a contributory factor to the BBB damage observed after Meth exposure and that this damage is manifested as large molecule extravasation into the brain parenchyma and phosphorylation-dependent decreases in endothelial tight junction proteins. The translational rationale is to develop a novel and feasible neuroprotective strategy that targets neuroinflammation and is either prophylactic or can rescue the BBB from the harmful consequences resulting from the combined exposures to stress and Meth. Three distinct but complementary aims will address our hypothesis. Specific Aim 1 will identify the duration and degree of BBB permeability after the serial exposure to chronic stress and the self administration of Meth. Specific Aim 2 will examine the underlying causes of BBB permeability and will elucidate the time-dependent neuroinflammatory mechanisms responsible for the permeability changes. Specific Aim 3 will determine the consequences of the increased permeability of the BBB produced by the serial exposure to stress and Meth by examining the augmentation of neuroinflammation caused by entrance of the oral bacterium associated with "Meth mouth", p. gingivalis, into the brain. The findings will have an overall positive impact because the determination of the causes and consequences of a breach in the BBB can guide the design of future therapeutic strategies for the treatment of METH neurotoxicity and overdose. The hope is to fundamentally advance the field of drug abuse-induced brain injury in general, by broadening the significance of Meth toxicity to include the long-term impact on the cerebral vasculature endothelium and thereby begin to understand the far reaching neurobiological consequences associated with this effect.

描述（由申请人提供）：对甲基苯丙胺（METH）的滥用及其对脑神经递质系统的毒性众所周知，但其对其他靶标（例如脑微血管内皮细胞）的潜在损害被忽略了。此外，由于METH与其他健康问题（例如压力和创伤后应激障碍）高度合并，因此必须了解压力和甲基甲基苯应之间的机械基础，以便可以开发有效的治疗策略，以有效地治疗滥用甲基甲基甲基苯丙胺的范围。该提案研究了与压力和滥用甲基甲基甲基苯丙胺的合并症相关的新结果，这是对血脑屏障（BBB）和脑微血管内皮细胞的长期损害所证明的。长期目标是确定与这种合并症相关的综合作用，并评估由于滥用甲基苯丙胺而导致的压力引起的脑损伤增加所产生的人类健康风险。我们的工作模型为假设提供了基础，即慢性应激诱导的神经炎症是甲基甲基甲基甲基甲基甲基苯乙丙胺后观察到的BBB损伤的一个因素，并且这种损害表现为大分子渗入脑实质中，而内皮性紧密连接蛋白中磷酸化依赖性依赖性降低。转化理由是开发一种新颖且可行的神经保护策略，该策略靶向神经炎症，是预防性的，或者可以从综合暴露于压力和甲基甲基甲基甲基体验所带来的有害后果中挽救BBB。三个不同但互补的目标将解决我们的假设。特定的目标1将确定慢性应激和甲基甲基苯应施用后，BBB渗透性的持续时间和程度。具体目标2将检查BBB渗透性的根本原因，并将阐明导致渗透率变化的时间依赖性神经炎症机制。具体目标3将通过检查与“甲基酸嘴”相关的口腔细菌的进入引起的神经炎症的增强，从而确定通过串行暴露于压力和甲基甲酯产生的BBB渗透性增加的后果。牙龈，进入大脑。这些发现将产生总体积极的影响，因为确定BBB中违反的原因和后果可以指导未来治疗甲基毒性神经毒性和过量治疗的治疗策略。希望通过扩大甲基毒性的重要性，包括对脑血管内皮的长期影响，从而开始理解与这种作用相关的遥远的神经生物学后果，从而从根本上促进药物滥用引起的脑损伤领域。