Pathways to HIV-Associated Neurocognitive Disorders: A Systems Biology Approach

HIV 相关神经认知障碍的途径：系统生物学方法

• 批准号: 8145259
• 负责人: Steve Horvath
• 金额: $ 30.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145259
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Acquired Immunodeficiency Syndrome; Adult; Affect; Alcohol or Other Drugs use; Anti-Retroviral Agents; Biological; Biological Markers; Brain; Cell Count; Cells; Chronic; Cocaine; Cohort Studies; Complex; Data; Dementia; Disease; Equation; Etiology; Event; FCGR3B gene; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Markers; Genotype; HIV; Immunology; Impairment; Individual; Infiltration; Investigation; Lead; Mediating; Medicine; Methamphetamine; Methods; Modeling; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuropsychology; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Prevalence; Public Health; Resources; Severities; Systems Biology; T-Lymphocyte; Therapeutic; Validation; Viral Load result; Weight; brain tissue; clinical Diagnosis; cohort; cost; critical period; genome-wide; innovation; monocyte; network models; neurocognitive test; neuroinflammation; novel; prophylactic; protein expression; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite widespread use of intensive antiretroviral medicines. Up to 50% of HIV-infected individuals will develop some degree of HIV-related neurocognitive impairment during their lifetimes, ranging from mild deficits that do not significantly impact day-to-day functioning to debilitating dementia. HAND is likely the result of chronic neuroinflammation, mediated in large part by the infiltration of monocytes into the brain. This neuroinflammation, and subsequently the severity of HAND, are enhanced by use of stimulant drugs, including cocaine and methamphetamine. The cellular cascade of events associated with HIV-associated dementia has been well-described, including alterations in the phenotype of blood monocytes, and changes in gene expression and protein expression within brain tissue. However, the vast majority of HAND involves insidious, often chronic mild neurocognitive deficits that do not evolve into dementia. Despite this, the cellular changes associated with mild HAND have not yet been well-delineated. In the proposed study, we will apply innovative systems biology approaches to the investigation of mild HAND pathogenesis. We focus our investigation on circulating blood monocytes, as these cells are an early and key component of this pathogenesis. We will use integrated weighted gene co-expression network analysis (IWGCNA), developed by the co-PI/PD, to develop meaningful biological pathways derived from monocyte-specific gene expression microarrays, HAND-associated genetic markers, and clinical diagnosis of HAND. Using structural equation modeling, we will then determine how stimulant use and virologic biomarkers (e.g. viral load) modify these pathways. This analytic strategy will first be implemented on a large cohort of HIV-infected individuals from the Multicenter AIDS Cohort Study (MACS). We will then validate our findings on a separate cohort from the National Neurological AIDS Bank (NNAB). To accomplish this ambitious study, we have assembled a collaborative team that includes leaders in immunology, systems biology, neuroAIDS, neuropsychology, and genetics. Further, because we will be relying largely on existing resources and data, the monetary cost and patient burden necessary for the study are extraordinarily low. The results of the study will lead to greater understanding of the mechanisms involved in HAND, provide potential biomarkers of HAND, and identify targets for pharmaceutical prophylactics and therapeutics. PUBLIC HEALTH RELEVANCE: The impact of HIV-associated neurocognitive disorders (HAND) is substantial, as it is estimated to affect upwards of 50% of HIV-infected individuals at some point during their lives. Understanding the etiology of HAND, especially now that it has shifted to include primarily mild and chronic impairments, is paramount. This study seeks to identify biological pathways involved in mild HAND, and could lead to novel biomarkers and therapeutic targets.

描述（由申请人提供）：尽管广泛使用强化抗逆转录病毒药物，但与HIV相关的神经认知障碍（手）的患病率仍然很高。 高达50％的HIV感染者将在其一生中发展一定程度的HIV相关神经认知障碍，范围从无明显影响日常功能的轻度缺陷到使衰减痴呆症的衰弱。手很可能是慢性神经炎症的结果，很大程度上是由于单核细胞渗入大脑而在很大程度上介导的。 通过使用刺激性药物（包括可卡因和甲基苯丙胺），这种神经炎症以及随后的手的严重程度得到了增强。与与HIV相关痴呆相关的事件的细胞级联已经被很好地描述了，包括血液单核细胞表型的改变，以及脑组织中基因表达和蛋白质表达的变化。但是，绝大多数手涉及阴险，通常是慢性轻度神经认知缺陷，这些缺陷不会演变为痴呆症。 尽管如此，与轻度手相关的细胞变化尚未得到很好的限制。在拟议的研究中，我们将应用创新的系统生物学方法来研究轻度手部发病机理。我们将研究重点放在循环血单核细胞上，因为这些细胞是该发病机理的早期和关键组成部分。 我们将使用Co-PI/PD开发的综合加权基因共表达网络分析（IWGCNA）来开发从单核细胞特异性基因表达微阵列，手工相关的遗传标记物和手册临床诊断中得出的有意义的生物学途径。然后，我们将使用结构方程建模，然后确定刺激性使用和病毒生物标志物（例如病毒载荷）如何修改这些途径。该分析策略将首先在多中心艾滋病队列研究（MAC）的大量HIV感染者队列上实施。然后，我们将在与国家神经艾滋病银行（NNAB）单独的同类群体上验证我们的发现。 为了完成这项雄心勃勃的研究，我们组建了一个合作团队，其中包括免疫学，系统生物学，神经助理，神经心理学和遗传学领域的领导者。此外，由于我们将主要依靠现有的资源和数据，因此该研究所需的货币成本和患者负担极低。 该研究的结果将使人们对涉及的机制，提供潜在的生物标志物，并确定药物预防药物和治疗剂的靶标。 公共卫生相关性：与艾滋病毒相关的神经认知障碍（手）的影响很大，因为据估计，它在他们一生中的某个时候会影响50％以上的艾滋病毒感染者。了解手的病因，尤其是现在它已经转移到主要是轻度和慢性障碍的情况下是至关重要的。这项研究旨在鉴定与轻度手相关的生物学途径，并可能导致新型的生物标志物和治疗靶标。