BUPROPION HIV

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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是临床和公共卫生重要性日益增加的一个领域。本申请集中于HIV-1包膜神经毒素gp 120、α 7烟碱乙酰胆碱受体（α 7 nAChR）和尼古丁之间的新型相互作用。与HIV血清阳性的非吸烟者相比，HIV血清阳性的吸烟者显示出更高的病毒载量和更低的CD 4+细胞计数（Wojna等人，2007），这可能是尼古丁在免疫细胞中慢性激活上调的α 7 nAChR（由于gp 120慢性暴露）的结果，这可能导致免疫细胞的钙超载并最终导致凋亡。我们假设与α 7 nAChR相互作用的药物 功能性可以潜在地减轻可能由上调的α 7 nAChR的慢性尼古丁刺激引起的病理后果。 这些研究的长期目标是确定基于使用烟碱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特征，并研究戒烟药物是否可用作HIV感染期间的预防性治疗。使用拮抗剂的基本原理是，通过干扰上调的α 7 nAChR活性，预期拮抗剂减少钙超载和潜在相关的细胞凋亡。安非他酮将作为模型α 7 nAChR拮抗剂进行研究。我们在nAChR和MDM研究方面的丰富经验，我们在共聚焦成像和电生理技术方面的专业知识，以及我们与UPR-MSC NeuroAIDS项目临床医生的密切合作，使我们处于有利地位，能够成功开展拟议的研究并及时完成工作。我们提出以下目标：（1）阐明α 7 nAChR拮抗剂安非他酮是否保护MDM免受gp 120暴露引起的钙超载，（2）确定安非他酮对MDM中激动剂诱导的单通道<$7 nAChR电流的影响，和（3）使用流式细胞术将MDM中gp 120诱导的<$7 nAChR上调与凋亡相关联，并确定治疗浓度的安非他酮是否保护免于凋亡。

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.