PROTEASOME AND PARKIN AS DRUG TARGETS AGAINST METHAMPHETAMINE TOXICITY

蛋白酶体和 Parkin 作为对抗甲基苯丙胺毒性的药物靶标

• 批准号: 9067300
• 负责人: Anna Moszczynska
• 金额: $ 33.86万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067300
• 关键词: 26S proteasome; Acute; Animals; Attenuated; Behavior; Blood - brain barrier anatomy; Brain; Brain Diseases; Cell Death; Cell Survival; Chronic; Clinical; Confocal Microscopy; Corpus striatum structure; Data; Development; Dissociation; Dose; Drug Targeting; Etiology; Evaluation; Exposure to; Goals; HIV-1; Health; Human; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Injection of therapeutic agent; Intervention; Knock-out; Lead; Link; Mediating; Methamphetamine; Methods; Molecular; Neurons; Overdose; Oxidative Stress; Parkinson Disease; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Process; Proteins; Rattus; Recovery; Research; Role; System; Therapeutic; Toxic effect; Ubiquitin; Up-Regulation; Variant; base; combat; design; dopaminergic neuron; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; methamphetamine abuse; methamphetamine effect; methamphetamine use; methamphetamine user; molecular drug target; multicatalytic endopeptidase complex; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; novel; novel strategies; overexpression; parkin gene/protein; prevent; protein aggregate; psychostimulant; synuclein; targeted treatment; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Methamphetamine (METH) is a highly addictive psychostimulant drug that is neurotoxic when taken at high doses chronically or acutely. METH selectively damages striatal dopaminergic terminals in experimental animals and humans. Despite years of active research on METH neurotoxicity, no specific medications have been developed to counteract the damaging effects that METH has on the brain. Due to its widespread abuse, there is a compelling need for effective pharmaceuticals that can protect and/or restore the brain from the toxic effects of acute METH overdose and chronic METH abuse. Thus, it is necessary to identify molecular drug targets in order to develop novel pharmaceuticals. My long-term goal is to develop neuroprotective therapies to treat the toxic effects of METH use. The goal of the proposed research is to better understand the molecular mechanisms regulating the ubiquitin-proteasome system in the METH-exposed rat brain and to determine whether two components of this system, proteasome and the E3 ligase parkin, are potential pharmaceutical targets that can be used to promote [survival and recovery] of dopaminergic terminals in vivo after toxic doses of [binge and chronic] METH. Both proteasome and parkin are decreased shortly after binge METH administration, and those deficits are also involved in the etiology of Parkinson's disease. We hypothesize that increasing their functions will provide neuroprotection in rats chronically and acutely exposed to METH. Specific Aim 1 will evaluate the relative roles of 20S and 26S proteasomes on the [survival of dopaminergic terminals and their recovery from binge and chronic] METH by using proteasomal inhibitors and a novel approach to regulate proteasomal activity, namely, systemic injections of TAT-tagged peptides that interfere with proteasomal assembly. TAT is a domain of the human immunodeficiency virus type 1 that rapidly crosses the blood brain barrier. These two forms of the proteasome behave differently upon exposure to METH- induced oxidative stress; thus, evaluation of their respective roles in METH neurotoxicity is warranted. Specific Aim 2 will evaluate the role of parkin in the [survival of and recovery from binge and chronic] METH using wild- type, parkin-overexpressing, and parkin knock-out rats. The role of parkin in the formation of intracellular inclusions in the nigrostriatal dopamine neurons will be investigated using immunohistochemistry and confocal microscopy. Specific Aim 3 will determine whether proteasomes and parkin are functionally linked in the METH-exposed rat brain. For clinical intervention purposes, it is important to know how variations in parkin levels influence 20S and 26S function and vice versa. These aims are conceptually linked as they investigate regulatory processes within the ubiquitin-proteasome system that may be important for [endogenous survival and recovery mechanisms] in dopamine neurons and, therefore, clinically important. The findings from the proposed research may lead to novel treatments for METH users.

描述（由申请人提供）：甲基苯丙胺（甲基苯丙胺）是一种高度上瘾的心理刺激性药物，当以长期或急性为单位时，具有神经毒性是神经毒性的。 METH选择性损害实验动物和人类中的纹状体多巴胺能末端。尽管多年来对甲基甲基毒性神经毒性进行了多年的积极研究，但尚未开发出特定的药物来抵消甲基甲基对大脑的破坏性影响。由于其广泛的滥用，因此需要有效的药物，可以保护和/或恢复大脑免受急性甲基甲基酸酯过量和慢性甲基甲基苯丙胺的毒性影响。因此，有必要识别分子药物靶标，以开发新的药物。我的长期目标是开发神经保护疗法来治疗使用甲基苯丙胺的毒性作用。拟议的研究的目的是更好地了解甲基甲基大鼠大脑中泛素 - 蛋白酶体系统的分子机制，并确定该系统的两个组成部分，蛋白酶体和E3连接酶Parkin是否是潜在的药物靶标，是可用于促进多巴胺素终结和促进毒素的毒性和回收率的[生存和恢复]的潜在药物。暴饮暴食后不久，蛋白酶体和帕金蛋白都会减少，这些缺陷也参与了帕金森氏病的病因。我们假设增加其功能将在长期和急性暴露于甲基苯酚的大鼠中提供神经保护。具体目标1将通过使用蛋白酶体抑制剂以及一种调节蛋白酶体活性的新方法来评估20s和26s蛋白酶体对[多巴胺能末端的存活以及它们从暴饮暴食和慢性慢性]中恢复的相对作用。 TAT是人类免疫缺陷病毒1型的结构域，可快速越过血脑屏障。这两种形式的蛋白酶体在暴露于METH诱导的氧化应激时行为不同。因此，有必要评估它们在甲基神经毒性中的作用。特定的目标2将评估帕金在使用野生型，过表达帕金的甲基甲基苯丙胺中的[来自暴饮暴食和慢性]甲基苯丙胺的生存和帕金敲除大鼠中的作用。 Parkin在黑质纹状体多巴胺神经元中形成细胞内夹杂物中的作用将使用免疫组织化学和共聚焦显微镜进行研究。特定的目标3将确定蛋白酶体和帕金蛋白是否在甲基暴露的大鼠脑中有功能连接。出于临床干预目的，重要的是要了解帕金水平的变化如何影响20S和26S功能，反之亦然。这些目标在概念上是联系，因为它们研究了多巴胺神经元中[内源性生存和恢复机制]可能很重要的泛素 - 蛋白酶体系统中的调节过程，因此在临床上很重要。拟议研究的发现可能会导致冰毒使用者的新型治疗方法。