Molecular Mechanisms & Therapy for Cocaine Abuse in HAND

分子机制

基本信息

批准号：
8334487
负责人：
Shilpa J. Buch
金额：
$ 20.04万
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 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334487
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.

描述（由申请人提供）：越来越清楚的是，HIV-1感染和药物滥用是相互联系的流行病。实际上，已建议可卡因经常被HIV-1感染的患者滥用，并加快疾病发病机理，HIV-1相关的神经系统疾病（HARD）主要是由于神经胶质激活增加和神经炎症的结果，而神经炎症是响应于HIV蛋白介导的CNS中毒性因素释放的响应。在中枢神经系统中诱导的已知介体中，我们在微阵列分析中确定了血小板衍生的生长因子（PDGF）是与手相关的因素。最近，PDGF从星形胶质细胞释放到内皮细胞，作为神经退行性疾病（例如中风）中的脑血管渗透性。此外，可卡因被认为是破坏血脑屏障的因素。根据这些发现，我们假设TAT和/或可卡因介导的星形胶质细胞及其附近的内皮细胞对PDGF-BB的诱导可能导致内皮屏障的破坏，从而增加HIV-1感染的可卡因虐待者的手部病理学。 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.这些研究既新颖又是创新的，因为PDGF作为HIV TAT和可卡因毒性的介体的作用从未探索过，并且此外，测试PDGF中和抗体的疗效对持有可卡因虐待者的手患者的意义可能很大。