Molecular Mechanisms & Therapy for Cocaine Abuse in HAND

分子机制

基本信息

批准号：
8121834
负责人：
Shilpa J. Buch
金额：
$ 20.28万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121834
关键词：
AIDS Dementia Complex Accounting Acquired Immunodeficiency Syndrome Acute Address Affect American Astrocytes Attenuated Binding Blood - brain barrier anatomy Blood Vessels Brain Case Study Cause of Death Cells Cerebrum Cocaine Cocaine Abuse Cognitive deficits Coupled Developed Countries Development Disease Disease Progression Drug abuse Drug usage Encephalitis Endothelial Cells Epidemic Exhibits Foot Process Giant Cells Goals HIV HIV Envelope Protein gp120 HIV Infections HIV encephalitis HIV-1 Highly Active Antiretroviral Therapy Human Incidence Individual Infection Inflammation Mediators Inflammatory Injection of therapeutic agent Intervention Laboratory Study Lead Link Macaca Mediating Mediator of activation protein Microarray Analysis Modeling Molecular Morbidity - disease rate Mus Needle Sharing Neurocognitive Neurodegenerative Disorders Neurologic Organ Pathogenesis Pathologic Pathology Patients Permeability Pharmaceutical Preparations Platelet-Derived Growth Factor Prevalence Proteins Proto-Oncogene Proteins c-sis Quality of life RNA Rattus Risk Role Stroke Survival Rate Testing Therapeutic Therapeutic Intervention Tight Junctions Toxic effect Up-Regulation Viral Viral Proteins Virus astrogliosis attenuation base brain tissue cerebral atrophy cerebrovascular cocaine exposure daily functioning efficacy testing exposed human population global health human CREB1 protein in vivo innovation intravenous drug use macrophage mild neurocognitive impairment monolayer mortality motor disorder nervous system disorder neuroinflammation neurotoxic neutralizing antibody novel novel therapeutic intervention platelet-derived growth factor BB prevent receptor response simian human immunodeficiency virus tat Protein transmission process

项目摘要

DESCRIPTION (provided by applicant): It is becoming increasingly clear that HIV-1 infection and drug abuse are interlinked epidemics. In fact, cocaine, often abused by HIV-1 infected patients, has been suggested to hasten as well as worsen disease pathogenesis, HIV-1 associated neurological disorders (HAND) are primarily a result of increased glial activation, and neuroinflammation, in response to HIV protein mediated release of toxic factors in the CNS. Among the known mediators induced in the CNS, we have identified platelet-derived growth factors (PDGF) in our microarray analysis as a factor associated with HAND. More recently, PDGF released from the astrocytes proximal to the endothelial cells as a cerebrovascular permeant in neurodegenerative disorder such as stroke. Additionally, cocaine has been implicated as a factor that disrupts the blood brain barrier. Based on these findings we hypothesized that Tat and/or cocaine mediated induction of PDGF-BB from both the astrocytes and their neighboring endothelial cells, could lead to enhanced disruption of the endothelial barrier resulting in increased pathology of HAND in HIV-1 infected cocaine abusers. To address this hypothesis two specific aims are proposed: 1) Investigate the molecular mechanisms involved in Tat/cocaine-mediated expression of PDGF in astrocytes and endothelial cells and, 2) To test the therapeutic potential of PDGF neutralizing antibody as an intervention strategy in vivo using two complementary murine models of HAND exposed to cocaine. These studies are both novel and innovative in that the role of PDGF as a mediator of HIV Tat and cocaine toxicity has never been explored before and furthermore, the efficacy of testing PDGF neutralizing antibody can have far reaching implications for HAND patients that are cocaine-abusers. PUBLIC HEALTH RELEVANCE: HIV-1 infected individuals that abuse cocaine have increased risk of vascular changes that can result in increased complications of the CNS. This study proposes to explore how cocaine and HIV proteins together can increase the burden of a toxic mediator in the CNS and also aims to develop therapeutic interventions to inhibit vascular changed associated with cocaine and HIV-1.

描述（由申请人提供）：越来越明显的是，HIV-1 感染和药物滥用是相互关联的流行病。事实上，经常被 HIV-1 感染者滥用的可卡因被认为会加速和恶化疾病的发病机制，HIV-1 相关的神经系统疾病 (HAND) 主要是由于神经胶质细胞活化和神经炎症增加所致。 HIV 蛋白介导中枢神经系统中毒性因子的释放。在 CNS 中诱导的已知介质中，我们在微阵列分析中将血小板衍生生长因子 (PDGF) 鉴定为与 HAND 相关的因子。最近，PDGF从靠近内皮细胞的星形胶质细胞中释放出来，作为中风等神经退行性疾病中的脑血管渗透物。此外，可卡因也被认为是破坏血脑屏障的一个因素。基于这些发现，我们假设 Tat 和/或可卡因介导星形胶质细胞及其邻近内皮细胞诱导 PDGF-BB，可能导致内皮屏障破坏加剧，从而导致 HIV-1 感染的可卡因滥用者的 HAND 病理增加。为了解决这一假设，提出了两个具体目标：1) 研究星形胶质细胞和内皮细胞中 Tat/可卡因介导的 PDGF 表达的分子机制，2) 测试 PDGF 中和抗体作为体内干预策略的治疗潜力使用暴露于可卡因的两种互补的 HAND 小鼠模型。这些研究既新颖又创新，因为之前从未探讨过 PDGF 作为 HIV Tat 和可卡因毒性介质的作用，此外，测试 PDGF 中和抗体的功效可以对可卡因滥用者的 HAND 患者产生深远的影响。公共卫生相关性：滥用可卡因的 HIV-1 感染者会增加血管变化的风险，从而导致中枢神经系统并发症增加。本研究旨在探索可卡因和 HIV 蛋白如何共同增加中枢神经系统中有毒介质的负担，并旨在开发治疗干预措施来抑制与可卡因和 HIV-1 相关的血管变化。