Interaction of Alcohol with HIV-Protein

酒精与 HIV 蛋白质的相互作用

基本信息

批准号：
7681103
负责人：
Norman J Haughey
金额：
$ 35.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-27 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681103
关键词：
AIDS Dementia Complex Acute Adult Age-Years Alcohol abuse Alcohols Aspartate Astrocytosis Attention Attenuated Biochemistry Brain Calcium Cell membrane Cellular Membrane Ceramides Cessation of life Cholesterol Cholesterol Homeostasis Chronic Cognitive Coupling Death Domain Dementia Endoplasmic Reticulum Equilibrium Functional disorder Gangliosides Giant Cells Goals HIV HIV Envelope Protein gp120 HIV Infections HIV encephalitis HIV-1 Impaired cognition In Vitro Infection Kinetics Lead Lipid Peroxidation Membrane Membrane Microdomains Metabolism Modification Motor NR1 gene Neuronal Dysfunction Neurons Oxidants Oxidation-Reduction Pallor Pathogenesis Patients Phosphorylation Phosphorylation Site Point Mutation Principal Investigator Proteins Reporting Role Sales Severities Signal Transduction Site Sphingolipids Sphingomyelins Stabilizing Agents Sterols Structure Synapses Synaptic plasticity Testing Therapeutic Transgenic Mice Viral Withdrawal alcohol effect alcohol exposure aspartate receptor base brain cell chronic alcohol ingestion cooking design drug of abuse frontal lobe function functional group i-cholesterol in vivo Model innovation macrophage neuron loss neurotoxic prevent programs public health relevance receptor receptor function trafficking white matter

项目摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus type -1 (HIV-1) infection is the commonest cause of dementia in adults less than 40 years of age. Alcohol is a common drug of abuse in HIV-infected patients that can worsen the decline of frontal lobe function that is associated with HIV encephalitis. Our goals are to determine the mechanisms of neuronal dysfunction and death associated with alcohol abuse in the setting of HIV-dementia that are dependent on the pathological modification of ceramide and sterol content in neuronal membranes. Although a number of channelopathies have been identified in HIV-dementia, we have deliberately focused our attention on alterations in N-methyl-d-aspartate (NMDA) receptor function because of the importance of this excitatory receptor in neuronal dysfunction and death. Our preliminary findings suggest that the alcohol can rapidly alter the cholesterol and ceramide content of neuronal membranes, while the HIV-1 proteins gp120 and Tat alter the sphingomyelin and ceramide composition, and promote the trafficking of NMDA receptors to rafts. Based on these observations we hypothesize that alcohol may promote neuronal dysfunction in HIV-dementia by disorganizing the structure of lipid rafts and perturbing the function of raft-located NMDA receptors. Accordingly, pharmacological agents that stabilize ceramide and cholesterol metabolism may be neuroprotective by preventing the disorganization of lipid rafts. Using in vitro and in vivo models of HIV-dementia, we propose to determine the mechanisms of how alcohol dysregulates neuronal function in acute, chronic and withdrawal conditions. Public Health Relevance: Alcohol is a common drug of abuse in HIV-infected patients that can hasten the onset of dementia and worsen the severity of cognitive decline. Determination of how alcohol interacts with viral products to damage brain cells is critical for the rational design of therapeutics designed to protect brain functions.

描述（由申请人提供）：人类免疫缺陷病毒类型-1（HIV -1）感染是成年人不到40岁的成年人痴呆症的最常见原因。酒精是艾滋病毒感染患者的常见药物，可能会使与HIV脑炎有关的额叶功能的下降恶化。我们的目标是确定在艾滋病毒降解的情况下，神经元功能障碍和与酒精滥用相关的死亡的机制，这些机制取决于神经元膜中神经酰胺和固醇含量的病理修饰。尽管在HIV痴呆症中已经发现了许多通道病，但由于这种兴奋性受体在神经元功能障碍和死亡中的重要性，我们已故意将注意力集中在N-甲基-D-天冬氨酸（NMDA）受体功能的改变上。我们的初步发现表明，酒精可以迅速改变神经元膜的胆固醇和神经酰胺含量，而HIV-1蛋白GP120和TAT则改变了鞘磷脂和神经酰胺的组成，并促进将NMDA受体运输到Rafts上。基于这些观察结果，我们假设酒精可能会通过混乱脂质筏的结构并扰动筏上分离的NMDA受体的功能来促进HIV痴呆中的神经元功能障碍。因此，稳定神经酰胺和胆固醇代谢的药理学剂可以通过防止脂质筏的混乱来神经保护。我们提出使用体外和体内模型的HIV驱动模型，以确定酒精如何在急性，慢性和戒断条件下神经元功能失调的机制。公共卫生相关性：酒精是艾滋病毒感染患者的一种常见药物，可以加快痴呆症的发作并恶化认知能力下降的严重程度。酒精如何与病毒产物相互作用以损害脑细胞是至关重要的，这对于旨在保护脑功能的治疗剂的合理设计至关重要。