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: 7230650
• 负责人: ARUN VENKATESAN
• 金额: $ 18.37万
• 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/7230650
• 关键词: Adult; Aging; Animal Model; Anti-HIV Agents; Apoptosis; Astrocytes; Behavioral; Biological Models; Brain region; Cell Proliferation; Cell physiology; Cells; Classification; Cognitive; Cognitive deficits; Condition; Cultured Cells; 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; Oxidative Stress Pathway; Parahippocampal Gyrus; Pathogenesis; 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; career; cognitive function; dentate gyrus; design; drug of abuse; excitotoxicity; human CREB1 protein; in vivo; in vivo Model; inhibitor/antagonist; methamphetamine exposure; nerve stem cell; neurogenesis; neurotoxicity; nonhuman primate; novel; novel therapeutics; programs; 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）：美国目前正面临甲基苯丙胺（METH）滥用的流行。甲基苯丙胺滥用者患有各种神经认知缺陷，其病理生理学仍然知之甚少。此外，许多甲基苯丙胺滥用者的情况因同时发生人类免疫缺陷病毒（艾滋病毒）感染而变得复杂。与非药物滥用患者相比，滥用药物（包括METH）的HIV感染患者具有加速和更严重的神经认知功能障碍。因此，确定感染HIV的METH使用者神经功能障碍的潜在底物是至关重要的。直到最近人们才认识到，神经发生持续到成年。成年海马齿状回（DG）的神经发生可能在认知功能的长期维持中起重要作用。我们假设暴露于METH和HIV反式激活蛋白达特的表达通过引起神经祖细胞（NPC）的氧化和亚硝化应激来破坏神经发生。初步研究表明，无论是甲基和达特损害成年海马DG在体内的神经发生，而甲基有直接影响的NPC，达特的影响似乎是间接介导的。在拟议的研究中，我们将进一步表征这种损伤发生的细胞和分子机制，重点是氧化和亚硝化应激作为HIV和METH破坏神经发生的手段。此外，我们将研究几种治疗药物的潜力，以防止METH和HIV对神经发生的联合作用。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的治疗策略，以对抗METH使用者和HIV感染患者的神经功能障碍。重要的是，该提案还包括详细的职业发展计划。约翰霍普金斯大学神经病学系提供了一个高度协作和互动的环境，在神经艾滋病和药物滥用研究的特殊专业知识，以及大量的教育机会。这些因素，沿着我将在Avindra Nath博士和Hongjun Song博士的实验室接受的指导，将使我有机会成为一名成功的独立临床科学家。