Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV

甲基苯丙胺和艾滋病毒对成人海马神经发生的损害

• 批准号: 7825349
• 负责人: ARUN VENKATESAN
• 金额: $ 18.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825349
• 关键词: Adult; Aging; Animal Model; Anti-HIV Agents; Apoptosis; Astrocytes; Behavioral; Biological Models; Brain region; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Cognitive; Cognitive deficits; Dementia; Development Plans; Drug abuse; Environment; Epidemic; Experimental Animal Model; Exposure to; Functional disorder; Gerbils; Grant; HIV; HIV encephalitis; HIV-1; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Investigation; Knowledge; Laboratories; Lead; Learning; Light; Maintenance; Mediating; Memory; Methamphetamine; Mitochondria; Modeling; Molecular; Nervous System Physiology; Neurocognitive; Neurocognitive Deficit; Neurologic Dysfunctions; Neurology; Neurons; Nitric Oxide; Parahippocampal Gyrus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Process; Proliferating; Reactive Oxygen Species; Reporting; Research; Research Personnel; Role; Scientist; Stress; System; Therapeutic Agents; Tissues; Toxic effect; Transgenic Mice; United States; Viral; Viral Proteins; Virus Diseases; adult neurogenesis; career development; cognitive function; combat; dentate gyrus; design; drug of abuse; excitotoxicity; human CREB1 protein; in vivo; in vivo Model; inhibitor/antagonist; methamphetamine abuse; methamphetamine exposure; nerve stem cell; neurogenesis; neurotoxicity; nitrosative stress; non-drug; nonhuman primate; novel; novel therapeutics; oxidative damage; programs; subventricular zone; tat Protein

DESCRIPTION (provided by applicant): The United States is currently facing an epidemic of methamphetamine (METH) abuse. METH abusers suffer from a variety of neurocognitive deficits, the pathophysiology of which remains poorly understood. In addition, the condition of many METH abusers is complicated by the co-occurrence of human immunodeficiency virus (HIV) infection. HIV infected patients who abuse drugs, including METH, have accelerated and more severe neurocognitive dysfunction compared with non-drug-abusing patients. Therefore, it is of paramount importance to determine the substrate underlying neurologic dysfunction in METH users infected with HIV. Only recently has it been recognized that neurogenesis continues through adulthood. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus may play an important role in the long-term maintenance of cognitive function. We hypothesize that exposure to METH and expression of the HIV transactivator protein Tat disrupts neurogenesis by causing oxidative and nitrosative stress in neural progenitor cells (NPC). Preliminary studies suggest that both METH and Tat impair adult hippocampal DG neurogenesis in vivo; while METH has direct effects on NPCs, Tat's effects appear to be indirectly mediated. In the proposed studies, we will further characterize the cellular and molecular mechanisms by which this impairment occurs, focusing on oxidative and nitrosative stress as means by which HIV and METH disrupt neurogenesis. Additionally, we will investigate the potential of several therapeutic agents to protect against the combined effects of METH and HIV on neurogenesis. We will conduct our investigations using both cell culture and animal model systems. Ultimately, knowledge gained from these studies may assist in designing novel therapeutic strategies to combat the neurologic dysfunction in METH users and HIV-infected patients. Importantly, this proposal also includes a detailed career development plan. The Johns Hopkins Neurology Department provides a highly collaborative and interactive environment, exceptional expertise in neuro-AIDS and drug abuse research, and a host of educational opportunities. These factors, along with the guidance that I will receive in the laboratories of Drs. Avindra Nath and Hongjun Song, will grant me the opportunity to become a successful, independent clinician-scientist.

描述（由申请人提供）：美国目前面临甲基苯丙胺（甲基苯丙胺）滥用的流行。甲基滥用者患有多种神经认知缺陷，其病理生理学仍然知之甚少。另外，许多滥用者的状况因人免疫缺陷病毒（HIV）感染的同时存在而变得复杂。与非药水滥用的患者相比，滥用毒品的艾滋病毒感染患者（包括甲基甲基苯甲酸盐）具有加速且更严重的神经认知功能障碍。因此，确定感染HIV的甲基甲基功能障碍的底物是至关重要的。直到最近，人们才认识到神经发生一直持续到成年。海马齿状回（DG）中的成年神经发生在长期维持认知功能中可能起重要作用。我们假设暴露于METH和HIV反式激活蛋白TAT的表达通过引起神经祖细胞（NPC）引起氧化和硝化应激，从而破坏神经发生（NPC）。初步研究表明，甲基和TAT均损害了体内成年海马DG神经发生。甲基对NPC有直接影响，但TAT的效应似乎是间接介导的。在拟议的研究中，我们将进一步表征这种损害发生的细胞和分子机制，重点是氧化和硝化应激，是HIV和METH破坏神经发生的手段。此外，我们将研究几种治疗剂的潜力，以防止甲基甲基和HIV对神经发生的综合作用。我们将使用细胞培养和动物模型系统进行研究。最终，从这些研究中获得的知识可能有助于设计新颖的治疗策略，以打击甲基苯丙胺使用者和感染HIV的患者的神经功能障碍。重要的是，该建议还包括详细的职业发展计划。约翰·霍普金斯神经病学部提供了高度协作和互动的环境，在神经辅助和药物滥用研究方面的卓越专业知识以及许多教育机会。这些因素，以及我将在DR的实验室中获得的指导。 Avindra Nath和Hongjun Song将授予我成为成功的独立临床医生的机会。