HIV GP120 EFFECTS ON NEUROTRANSMISSION

HIV GP120 对神经传递的影响

• 批准号: 3416095
• 负责人: RICHARD J ZIEGLER
• 金额: $ 12.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3416095
• 关键词: AIDS; acetylcholine; action potentials; catecholamines; cerebrospinal fluid; choline; cyclic AMP; cyclic GMP; diacylglycerols; dielectric property; electrophysiology; fatty acid metabolism; glycoproteins; human immunodeficiency virus; inositol phosphates; membrane potentials; monoclonal antibody; nervous system infection; neurotransmitter metabolism; neurotransmitters; phosphatidate; phospholipase C; phospholipase D; phosphorylcholine; protein structure function; second messengers; tissue /cell culture; virus protein; voltage gated channel

The molecular mechanisms responsible for the central nervous system and peripheral nervous system disease associated with HIV infections are not well understood. One possibility is that the exogenous envelope glycoprotein gp12O is released from HIVinfected cells and alters the process of neurotransmission in a manner which adversely affects neural function. gp12O-like activity has been detected in the cerebrospinal fluid (CSF) of cognitively- impaired AIDS patients, indicating that HIV-infected choriod plexus, endothelial, and microglial cells could act as a source of exogenous gp12O in the nervous system. Recently, we obtained some results from a pilot research project funded by the American Foundation for AIDS Research which indicate that exogenous gp12O can affect at least two phenomena in human cells associated with neurotransmission: 1) the induction of the synthesis of the neuromodulatory second messenger molecule, cAMP, by vasoactive intestinal peptide, a neuropeptide found in nerve terminals within the cerebral cortex hippocampus, amygdaloid nucleus and hypothalamus; and 2) the evoked release of catecholamines from cultured human neuron-like cells. We are requesting monies to continue our pilot study which focused on identifying gp12O-induced alterations in the following processes associated with neurotransmission: 1) electrogenic mechanisms, 2) neurotransmitter metabolism, and 3) membrane receptormediated neuromodulatory second messenger synthesis. Specific electrogenic mechanisms to be studied include membrane potentials, capacitances, time constants, action potentials and responses to acetylcholine. Features of neurotransmitter metabolism to be studied include catecholamine content, release, synthesis, and granular storage. The second messengers to be analyzed are the following: cAMP, cGMP, inositol phosphates, diacylglycerol, choline, phosphorylcholine, and phosphatidic acid. In addition, we intend to determine 1) the regions of the gp12O molecule which are responsible for observed effects, and 2) the presence of similar activity in the CSF of AIDS patients. We envision that our observation will lead to additional grant proposals concerning more indepth investigations of gp12O-induced effects. This information can be important for designing therapeutic compounds and strategies for treatment of "neural AIDS."

负责中枢神经系统的分子机制， 与HIV感染相关的外周神经系统疾病 很好理解。一种可能性是， 糖蛋白gp 12 O从HIV感染的细胞中释放出来， 神经传递过程中的一种方式， 功能在脑脊液中检测到gp 12 O样活性 (CSF)认知障碍的艾滋病患者，表明艾滋病毒感染者， 脉络丛，内皮细胞和小胶质细胞可以作为一个来源， 外源性gp 12 O在神经系统。最近，我们得到了一些结果， 由美国艾滋病基金会资助的一个试点研究项目 研究表明，外源性gp 12 O可以影响至少两个 与神经传递相关的人类细胞中的现象：1） 诱导神经调节第二信使的合成 血管活性肠肽是一种神经肽， 大脑皮层海马、杏仁核内的神经末梢 和下丘脑;和2）诱发释放的儿茶酚胺从培养的 人类神经元样细胞 我们正在申请资金，以继续我们的试点研究，重点是 在以下相关过程中鉴定gp 12 O诱导的改变 与神经传递：1）生电机制，2）神经递质 膜受体介导的神经调节第二阶段 信使合成待研究的具体产电机制包括 膜电位、电容、时间常数、动作电位和 对乙酰胆碱的反应神经递质代谢的特点是 研究内容包括儿茶酚胺含量、释放、合成和颗粒 存储.待分析的第二信使如下：cAMP， cGMP、磷酸肌醇、甘油二酯、胆碱、磷酸胆碱和 磷脂酸此外，我们还打算确定1） gp 12 O分子，其负责观察到的效应，和2） 在AIDS患者的CSF中存在类似的活性。我们设想 我们的观察将导致更多的赠款建议， 深入研究gp 12 O诱导的效应。该信息可以 对于设计治疗化合物和治疗策略很重要 神经艾滋病。"