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: 9344570
• 负责人: CHRISTINA S MEADE
• 金额: $ 72.18万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344570
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Alcohol or Other Drugs use; American; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Behavioral; Biological; Biology; Blood - brain barrier anatomy; Brain; Brain imaging; CCL2 gene; Cannabinoids; Cerebrospinal Fluid; Cerebrum; Clinical; Cocaine; Cocaine Users; Collaborations; Comorbidity; Complex; Computational Biology; Computer Simulation; 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; Immune System and Related Disorders; 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; Modality; 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; daily functioning; drug of abuse; executive function; experience; immune function; immunoregulation; innovation; insight; marijuana use; marijuana user; monocyte; mortality; multidisciplinary; 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 即使在广泛联合抗逆转录病毒治疗的时代，超过一半的艾滋病毒感染患者 经历艾滋病毒相关的神经认知障碍(NCI)。NCI在一定程度上是由持久的神经- 激活的单核细胞和T细胞起致病作用的炎症。大麻和可卡因，两种 艾滋病毒感染者中最常见的滥用药物会导致神经和认知的改变 功能，并具有显著的免疫调节作用。虽然艾滋病毒感染和药物滥用的影响 关于免疫功能障碍和炎症、脑结构/功能和NCI的独立研究， 这些生物系统之间复杂的相互作用没有得到很好的描述。我们的前期工作 提示可卡因和大麻的使用对HIV感染者的NCI有不一致的影响，有差异 跨认知功能领域的影响。此外，研究表明，像可卡因这样的兴奋剂 诱导激活的免疫状态，而大麻具有抗炎作用。建立在先前工作的基础上 我们的多学科团队，在神经科学，药物成瘾，艾滋病毒免疫学， 和计算生物学，这项拟议的研究使用系统生物学的方法来研究 可卡因和大麻对HIV感染者免疫功能、脑结构/功能和神经认知的影响 人。我们的目标是：(1)确定可卡因和大麻使用在MRI上的独立和联合影响 测量大脑体积、白质完整性和功能连通性，以及行为测量 (2)量化大麻和大麻之间外周和中枢神经系统免疫功能的差异 以及(3)使用系统生物学方法将免疫学、神经成像和 将行为数据转换为多层预测模型。我们的指导性假设是可卡因能诱导一种免疫 导致大脑结构/功能改变和认知障碍的激活状态，而大麻 通过抗炎过程减弱这些影响。样本将包括150名感染艾滋病毒的成年人。 仅使用可卡因、仅使用大麻、可卡因和大麻，或既不使用可卡因又不使用大麻的感染者，由4个不同的 组(~37个/组)。在研究完成后，我们将产生一个全面的、多学科的数据集， 我们的系统生物学方法将为未来产生新的假说提供重要的见解 艾滋病毒和药物使用的复杂生物交叉点研究。这项提议既解决了 迫切需要确定与特定疾病相关的影响神经认知损害差异的因素 药物滥用的模式“[RFA-DA-16-013]和艾滋病指定资助的多个高优先主题， 包括对艾滋病毒相关并发症的调查，如神经系统并发症和了解 免疫功能障碍和艾滋病毒传播的基本生物学[NOT-15-137]。这个创新的项目已经 很有可能阐明艾滋病毒感染和药物滥用所通过的复杂生物机制 影响NCI，并为新的疗法和临床干预确定适当的目标。