Macrophages and dopamine: a role in NeuroAIDS

巨噬细胞和多巴胺：在神经艾滋病中的作用

基本信息

批准号：
7495386
负责人：
Peter Jesse Gaskill
金额：
$ 4.96万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495386
关键词：
AIDS neuropathy Affect Brain CCR5 gene CD4 Antigens CXCR4 Receptors CXCR4 gene Central Nervous System Diseases Cocaine Cognitive Data Dementia Development Dopamine Dopamine Agonists Dopamine Receptor Dopaminergic Agents Drug abuse Drug usage Drug user Eels Goals HIV Impairment In Vitro Incidence Individual Infection Intervention Kinetics Macaca Mediating Methamphetamine Minor Mitogen-Activated Protein Kinases Neuraxis Neurologic Neuropathogenesis Numbers Pathology Pharmaceutical Preparations Pharmacology Play Process Production Protein Kinase Inhibitors Public Health Range Role SIV Severities Signal Pathway Signal Transduction Source Surface T-Lymphocyte Time Viral Viral Physiology Virion Virus Virus Diseases Virus Replication cellular targeting dopamine system drug abuser drug of abuse extracellular macrophage monocyte motor disorder nervous system disorder neuropathology neurotoxic protein kinase inhibitor research study

AIDS neuropathy Affect Brain CCR5 gene CD4 Antigens CXCR4 Receptors CXCR4 gene Central Nervous System Diseases Cocaine Cognitive Data Dementia Development Dopamine Dopamine Agonists Dopamine Receptor Dopaminergic Agents Drug abuse Drug usage Drug user Eels Goals HIV Impairment In Vitro Incidence Individual Infection Intervention Kinetics Macaca Mediating Methamphetamine Minor Mitogen-Activated Protein Kinases Neuraxis Neurologic Neuropathogenesis Numbers Pathology Pharmaceutical Preparations Pharmacology Play Process Production Protein Kinase Inhibitors Public Health Range Role SIV Severities Signal Pathway Signal Transduction Source Surface T-Lymphocyte Time Viral Viral Physiology Virion Virus Virus Diseases Virus Replication cellular targeting dopamine system drug abuser drug of abuse extracellular macrophage monocyte motor disorder nervous system disorder neuropathology neurotoxic protein kinase inhibitor research study

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项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to increase the understanding of the mechanisms contributing the exacerbation of neurological complications in Human Immunodeficiency Virus (HIV) infected drug abusers. The use of dopaminergic drugs, such as cocaine and methamphetamine, increases both the incidence and severity of HIV-induced neurological disease in HIV infected individuals. These drugs act by increasing extracellular dopamine levels in the central nervous system (CMS). Studies show that increased extracellular dopamine exacerbates HIV induced CMS pathology, but the mechanisms that mediate this effect are not fully characterized. Macrophages, the major target for HIV in the CMS, also play a central role in the neuropathology of HIV infection. The preliminary data in this proposal show that dopamine treatment increases HIV replication in macrophages, and demonstrate the presence of dopamine receptors on the surface of the eels. These data indicate that dopamine may play a direct role in the development of HIV induced CMS pathology through dopamine mediated modulation of HIV infection of macropahges. To determine the mechanism mediating this effect, studies in this proposal will fully characterize the pharmacology and kinetics of dopamine-mediated increase in HIV replication in macrophages. HIV infection in the presence of dopamine receptor agonists and antagonists will determine which dopamine receptors mediate the increase in HIV replication in macrophages. To examine the mechanism mediating this effect, studies will examine crosstalk between the active dopamine receptors and the HIV receptor CD4, and coreceptors CXCR4 and CCR5 as well as dopamine-induced alterations in the viral entry, integration, and budding processes. Experiments will also use protein kinase inhibitors during HIV infection to examine the signaling pathways involved in dopamine enhanced HIV replication. Defining the mechanisms by which dopamine increases HIV replication in macrophages will contribute to the understanding and treatment of the heightened incidence and severity of neurological disease among HIV infected drug users. PUBLIC HEALTH RELEVANCE: HIV infection can result in a variety of neurological complications that are exacerbated by drugs of abuse. Defining the mechanisms by which drug abuse increases the incidence and severity of HIV induced neurological complications will increase the understanding of HIV infection in the brain and help to develop intervention strategies to limit the devastating consequences of neurologic impairment in HIV infected drug users.

描述（由申请人提供）：该提案的目的是增加对人类免疫缺陷病毒（HIV）感染药物滥用者神经系统并发症加剧的机制的理解。多巴胺能药物（例如可卡因和甲基苯丙胺）的使用增加了HIV感染个体中HIV诱导的神经系统疾病的发病率和严重程度。这些药物通过增加中枢神经系统（CMS）中的细胞外多巴胺水平来起作用。研究表明，增加细胞外多巴胺加剧了HIV诱导的CMS病理学，但是介导这种作用的机制尚未完全表征。巨噬细胞是CMS中HIV的主要靶标，在HIV感染的神经病理学中也起着核心作用。该提案中的初步数据表明，多巴胺治疗会增加巨噬细胞中的HIV复制，并证明在鳗鱼表面上存在多巴胺受体。这些数据表明，多巴胺可能通过多巴胺的HIV感染调节艾滋病毒诱导的CMS病理发育而直接作用。为了确定介导这种作用的机制，该提案中的研究将充分表征多巴胺介导的巨噬细胞中HIV复制增加的药理学和动力学。在多巴胺受体激动剂和拮抗剂存在下，HIV感染将确定哪种多巴胺受体介导巨噬细胞中HIV复制的增加。为了检查介导这种作用的机制，研究将检查活性多巴胺受体与HIV受体CD4，CORECEPTORS CXCR4和CCR5之间的串扰，以及多巴胺诱导的病毒进入，整合和萌芽过程的变化。实验还将在HIV感染期间使用蛋白激酶抑制剂，以检查涉及多巴胺增强HIV复制的信号传导途径。定义多巴胺增加巨噬细胞中HIV复制的机制将有助于理解和治疗HIV感染的药物使用者的神经系统疾病的发病率和严重程度的增强。公共卫生相关性：艾滋病毒感染会导致各种神经系统并发症，这些并发症会因滥用药物而加剧。定义药物滥用增加艾滋病毒诱发的神经系统并发症的发病率和严重性的机制将增加对大脑中艾滋病毒感染的理解，并有助于制定干预策略，以限制艾滋病毒感染药物使用者的神经系统损害的毁灭性后果。