A Systems Biology Approach to HIV-associated Neurocognitive Impairment: Role of Drug Abuse and Neuroinflammation

HIV 相关神经认知障碍的系统生物学方法：药物滥用和神经炎症的作用

• 批准号: 9977138
• 负责人: CHRISTINA S MEADE
• 金额: $ 60.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977138
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Alcohol or Other Drugs use; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Behavioral; Biological; Biology; Blood - brain barrier anatomy; Brain; Brain imaging; CCL2 gene; Cannabinoids; Cerebrospinal Fluid; Cerebrum; Clinical; Cocaine; Cocaine Users; Collaborations; Complex; Computational Biology; Computer Models; Corpus Callosum; Data; Data Set; Development; Drug Addiction; Drug abuse; Exhibits; Fostering; Funding; HIV; HIV Infections; HLA-DR Antigens; High Prevalence; Illicit Drugs; Immune; Immune System Diseases; Immunologics; Immunology; Impaired cognition; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intervention; Investigation; Joints; K-Series Research Career Programs; Lead; Leukocytes; Link; Macrophage Activation; Magnetic Resonance Imaging; Marijuana; Measures; Memory; Morbidity - disease rate; Neopterin; Neurocognition; Neurocognitive Deficit; Neurologic; Neurophysiology - biologic function; Neuropsychological Tests; Neurosciences; Outcome; Parietal; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral; Persons; Pharmaceutical Preparations; Play; Process; Production; Research; Research Personnel; Role; Sampling; Science; Structure; Substance abuse problem; System; Systems Biology; T-Lymphocyte; TNF gene; Testing; Therapeutic; United States National Institutes of Health; Vascular Permeabilities; Work; antiretroviral therapy; behavior measurement; biological systems; cocaine use; cognitive function; comorbidity; daily functioning; drug of abuse; executive function; experience; immune function; immunoregulation; innovation; insight; marijuana use; marijuana user; monocyte; mortality; multidisciplinary; multimodality; neurobehavioral; neurocognitive test; neurofilament; neuroimaging; neuroinflammation; new therapeutic target; non-drug; novel; predictive modeling; processing speed; programs; public health relevance; relating to nervous system; sound; time use; transmission process; white matter

Project Summary Even in the era of widespread combination antiretroviral therapy, over half of HIV-infected patients experience HIV-associated neurocognitive impairment (NCI). NCI is driven in part by persistent neuro- inflammation with activated monocytes and T cells playing pathogenic roles. Marijuana and cocaine, two of the mostly commonly abused drugs among HIV-infected persons, cause alterations in neural and cognitive functioning, and have significant immunomodulatory effects. While the effects of HIV infection and drug abuse on immune dysfunction and inflammation, brain structure/function, and NCI have been independently studied, the complex interactions between these biological systems are poorly characterized. Our preliminary work suggests that cocaine and marijuana use have discordant effects on NCI in persons with HIV, with differential impacts across domains of cognitive function. In addition, research has shown that stimulants like cocaine induce an activated immune state, whereas marijuana has anti-inflammatory effects. Building on the prior work of our multi-disciplinary team, with complementary expertise in neuroscience, drug addiction, HIV immunology, and computational biology, the proposed research uses a systems biology approach to investigate the effects of cocaine and marijuana on immune function, brain structure/function, and neurocognition in HIV-infected persons. We aim to: (1) identify the independent and joint effects of cocaine and marijuana use on MRI measures of cerebral volume, white matter integrity, and functional connectivity, and on behavioral measures of neurocognition; (2) quantify differences in peripheral and CNS immune function between marijuana and cocaine users; and (3) employ a systems biology approach to integrate immunology, neuroimaging, and behavioral data into a multi-level predictive model. Our guiding hypothesis is that cocaine induces an immune activated state that causes alterations in brain structure/function and cognitive impairment, while marijuana attenuates these effects through anti-inflammatory processes. The sample will include 150 adults with HIV infection who use cocaine only, marijuana only, cocaine and marijuana, or neither drug, comprising 4 distinct groups (~37/group). At study completion, we will have produced a comprehensive, multi-disciplinary dataset, and our systems biology approach will provide significant insights to generate novel hypotheses for future research on the complex biological intersection of HIV and substance use. This proposal addresses both a critical need to identify “factors that impact differences in neurocognitive impairment in association with specific patterns of substance abuse” [RFA-DA-16-013] and multiple high priority topics for AIDS-designated funding, including investigation of HIV-associated comorbidities such as neurological complications and understanding the basic biology of immune dysfunction and HIV transmission [NOT-15-137]. This innovative project has strong potential to elucidate the complex biological mechanisms through which HIV infection and drug abuse impact NCI, and to identify appropriate targets for novel therapeutics and clinical interventions.

项目摘要 即使在宽度组合抗逆转录病毒疗法的时代，超过一半的HIV感染患者 经验与HIV相关的神经认知障碍（NCI）。 NCI部分由持续的神经驱动 活化的单核细胞和T细胞发炎，发挥致病作用。大麻和可卡因，其中两个 艾滋病毒感染者中通常通常滥用药物，导致神经和认知的改变 功能，并具有明显的免疫调节作用。而艾滋病毒感染和吸毒的影响 关于免疫功能障碍和注射，大脑结构/功能和NCI已独立研究， 这些生物系统之间的复杂相互作用的特征很差。我们的初步工作 表明可卡因和大麻的使用对艾滋病毒患者的NCI有不一致的影响， 认知功能领域的影响。此外，研究表明可卡因等兴奋剂 诱导活化的免疫状态，而大麻具有抗炎作用。基于先前的工作 我们的多学科团队拥有神经科学，药物成瘾，艾滋病毒免疫学方面的完整专业知识， 和计算生物学，拟议的研究采用系统生物学方法来研究影响 可卡因和大麻关于HIV感染的免疫功能，大脑结构/功能和神经认知 人。我们的目标是：（1）确定可卡因和大麻对MRI的独立和关节影响 脑体积，白质完整性和功能连接性以及行为测量的测量 神经认知； （2）量化大麻和中枢神经系统免疫功能的差异 可卡因用户； （3）采用系统生物学方法来综合免疫学，神经影像学和 行为数据成多层预测模型。我们的指导假设是可卡因诱导免疫 激活状态会导致大脑结构/功能和认知障碍的改变，而大麻 通过抗炎过程减轻这些影响。样本将包括150名艾滋病毒的成年人 仅使用可卡因，仅大麻，可卡因和大麻或两种药物的感染 组（〜37/组）。在学习完成时，我们将生成一个全面的多学科数据集， 我们的系统生物学方法将提供重要的见解，以为未来产生新颖的假设 研究HIV和药物使用的复杂生物学交集。该提议既解决 确定“影响神经认知障碍差异的因素 滥用药物的模式” [RFA-DA-16-013]和艾滋病指定资金的多个高优先级主题， 包括调查与HIV相关的合并症，例如神经系统并发症和理解 免疫功能障碍和HIV传播的基本生物学[NOT-15-137]。这个创新的项目有 阐明艾滋病毒感染和药物滥用的复杂生物学机制的强大潜力 影响NCI，并确定新型治疗和临床干预措施的适当靶标。