Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV

描述（由申请人提供）：美国目前正面临着甲基苯丙胺（冰毒）滥用的流行病。冰毒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，许多冰毒滥用者的病情因人类免疫缺陷病毒（HIV）感染的共同发生而复杂化。与非药物滥用患者相比，滥用药物（包括冰毒）的HIV感染患者神经认知功能障碍加速且更严重。因此，确定感染HIV的冰毒使用者神经功能障碍的底物至关重要。直到最近，人们才认识到神经发生会持续到成年期。海马齿状回（DG）的成人神经发生可能在认知功能的长期维持中起重要作用。我们假设暴露于甲基安非他明和HIV反激活蛋白Tat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，甲基苯丙胺和丙胺素均对体内成年海马DG神经发生有损害；虽然冰毒对npc有直接影响，但塔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，重点关注氧化和亚硝化应激作为HIV和甲基安非他明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，以防止甲基苯丙胺和艾滋病毒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来对抗冰毒使用者和hiv感染患者的神经功能障碍。重要的是，这份提案还包括详细的职业发展计划。约翰霍普金斯大学神经内科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方面拥有卓越的专业知识，以及大量的教育机会。这些因素，以及我将在实验室得到的博士的指导。Avindra Nath和Hongjun Song，将给我机会成为一个成功的，独立的临床医生和科学家。

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.