BUPROPION HIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 烟草使用与艾滋病毒/艾滋病流行之间的联系代表着一个日益重要的临床和公共卫生领域。目前的应用集中在HIV-1包膜神经毒素gp120、A7烟碱型乙酰胆碱受体(A7nAChR)和尼古丁之间的一种新的相互作用。与HIV血清阳性的不吸烟者相比，HIV血清阳性吸烟者表现出更高的病毒载量和更低的CD4+细胞计数(Wojna等人，2007年)，这可能是尼古丁慢性激活免疫细胞中上调的A7nAChR(由于gp120慢性暴露)的结果，这可能导致免疫细胞钙超载并最终导致细胞凋亡。我们假设与A7 nAChR相互作用的药物 功能可能会减轻慢性尼古丁刺激上调的A7 nAChR所导致的病理后果。 这些研究的长期目标是确定基于尼古丁受体拮抗剂的戒烟治疗是否会改善HIV血清阳性吸烟者的免疫学状况，并调查戒烟药物是否可以作为HIV感染期间的辅助治疗。使用拮抗剂的理由是，通过干扰上调的A7nAChR活性，拮抗剂有望减少钙超载和潜在的相关细胞凋亡。安非他酮将作为模型A7nAChR拮抗剂进行研究。我们在nAChRs和MDM研究方面的丰富经验，我们在共焦成像和电生理技术方面的成熟专业知识，以及我们与UPR-MSC神经艾滋病计划的临床医生的密切合作，使我们处于有利地位，能够成功地实施拟议的研究并及时完成工作。我们提出了以下目标：(1)阐明A7nAChR拮抗剂安非他酮是否能保护MDM免受gp120刺激所致的钙超载；(2)确定安非他酮对激动剂诱导的MDM单通道nAChR电流的影响；(3)用流式细胞仪检测gp120诱导的MDM中7nAChR上调与细胞凋亡的关系，并确定治疗浓度的安非他酮是否具有抗凋亡作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The association between tobacco use and HIV/AIDS epidemics represents an area of growing clinical and public health importance. The present application focuses on a novel interaction between the HIV-1 envelope neurotoxin gp120, the a7 nicotinic acetylcholine receptor (a7 nAChR), and nicotine. HIV seropositive smokers display higher viral loads and lower CD4+ cell counts than HIV seropositive nonsmokers (Wojna et al., 2007) which may be the result of chronic activation of the upregulated a7 nAChR (due to gp120 chronic exposure) in immune cells by nicotine which could lead to calcium overloading of immune cells and ultimately apoptosis. We hypothesize that drugs which interefere with the a7 nAChR functionality could potentially alleviate the pathological consequences that may result from the chronic nicotine stimulation of the upregulated a7 nAChR. The long-term goal of these studies is to define whether a smoking cessation therapy based on the use of a nicotinic receptor antagonist will improve the immunological profile of HIV-seropositive smokers and to investigate whether smoking cessation medication can be used as adjunctive therapy during HIV infection. The rationale for using antagonists is that by interfering with the upregulated a7 nAChR activity, antagonists are expected to reduce calcium overloading and the potentially related apoptosis. Bupropion will be studied as a model a7 nAChR antagonist. Our extensive experience in the study of nAChRs and MDMs, our established expertise in confocal imaging and electrophysiological techniques, and our strong collaborations with clinicians from the NeuroAIDS Program at UPR-MSC place us in a priviledged position to carry out the proposed studies successfully and complete the work in a timely manner. We propose the following aims: (1) To elucidate whether a7 nAChR antagonist bupropion protects MDMs against calcium overloading due to gp120 exposure, (2) To determine the effects of bupropion on agonist-induced single-channel ¿7 nAChR currents in MDMs, and (3) To correlate the gp120-induced ¿7 nAChR upregulation in MDMs with apoptosis using flow cytometry and determine whether bupropion at therapeutic concentrations protects against apoptosis.