A multi-systems study of HIV neuropathogenesis: genetics-neuropathology-behavior

HIV神经发病机制的多系统研究：遗传学-神经病理学-行为

• 批准号: 8695488
• 负责人: ANDREW J LEVINE
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695488
• 关键词: AIDS neuropathy; Affect; Age; Alcohol or Other Drugs use; Amyloid deposition; Anti-Retroviral Agents; Astrocytes; Behavior; Behavioral; Brain; Brain region; Characteristics; Chronic; Clinical; Cognitive; Collaborations; Dementia; Disease; Epidemiology; Equation; Event; Exogenous Factors; Future; Genes; Genetic; Genetic Predisposition to Disease; Genotype; HIV; Hepatitis C; Hippocampus (Brain); Image; Immunohistochemistry; Impairment; Individual; Infection; Infiltration; Influentials; International; Lead; Link; Measures; Mission; Modeling; Molecular; Nature; Neurocognitive; Neurocognitive Deficit; Neuropathogenesis; Outcome; Outcome Study; Paper; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological; Prevalence; Procedures; Proteins; Quality of life; Regression Analysis; Relative (related person); Research; Resources; Risk; Sampling; Severities; Synapses; System; United States; United States National Institutes of Health; Universities; Variant; Viral Load result; antiretroviral therapy; base; behavioral impairment; brain tissue; case control; clinical Diagnosis; cohort; design; frontal lobe; functional disability; genetic risk factor; genetic variant; immune activation; improved; innovation; macrophage; meetings; neurobehavioral; neuropathology; putamen

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) is near 50% despite the widespread use of combined antiretroviral therapy (cART). HAND is a clinical diagnosis based on neurocognitive impairments ranging in severity from mild neurocognitive deficits to a debilitating dementia. HAND is the result of a chronic neuroinflammatory state fueled by host immune activation; however, the key pathophysiological pathways involved remain unclear. In recent years, a small number of host genetic susceptibility loci have been identified that increase risk for HAND or influence its course, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis. However, all studies of HAND-related genetic susceptibility loci have relied solely on clinical outcomes; nothing is known of what pathophysiological changes these genetic variants cause. An innovative approach for determining the pathophysiological mechanisms through which genetic susceptibility loci influence HAND is to examine their influence on neuropathological intermediate phenotypes, or NIPs. At its most basic level, HAND is believed to be the end result of a sequence of physiological events that commences with HIV-induced cellular changes that are modified by genetic factors. In the context of the present study, we deem quantifiable neuropathological changes that occur proximal to the beginning of this causal chain of HAND pathogenesis as the NIPs necessary for the behavioral impairments characteristic of HAND. There exist a number of candidate NIPs that are associated with HAND, including synaptodendritic simplification; macrophage infiltration; microglial and astrocyte activation, and beta-amyloid deposition. Through examining the relationship between genetic susceptibility loci and NIPs in brain tissue derived from a clinically well-characterized cohort, it will be possible t determine 1) which genetic variants are biologically relevant to HAND, 2) the pathophysiological mechanisms through which they exert their effect on the neurobehavioral phenotypes, and 3) the relative importance of NIPs as underlying causative factors of HAND. This study is highly relevant to the mission of NIH to elucidate the physiological mechanisms leading to HAND. To accomplish our aims, we will use immunohistochemistry and high throughput quantification procedures to characterize NIPs across multiple brain regions. Our aim is to determine the extent to which genotype and important co-factors (e.g., age, substance use, cART use) modify these NIPs. Our second aim will determine the linear causative relationship between genetic susceptibility loci, NIPs, and neurocognitive impairment. Towards this end we will use Network Edge Orienting to determine the causative relationship between genotype and NIPs. This will be integrated with structural equation modeling, thus allowing creation of a comprehensive pathway model of HAND that includes genotype, NIPs, neurocognitive functioning, and important co-factors.

描述（由申请人提供）： 尽管广泛使用联合抗逆转录病毒疗法 (cART)，但 HIV 相关神经认知障碍 (HAND) 的患病率仍接近 50%。 HAND 是一种基于神经认知障碍的临床诊断，其严重程度从轻度神经认知缺陷到衰弱性痴呆。 HAND 是由宿主免疫激活引发的慢性神经炎症状态的结果；然而，所涉及的关键病理生理途径仍不清楚。近年来，已发现少数宿主遗传易感性位点会增加 HAND 风险或影响其病程，这表明对其基因产物参与的生理途径的扰动会改变 HAND 发病机制。然而，所有关于 HAND 相关遗传易感性位点的研究都仅依赖于临床结果；我们不知道这些基因变异会引起什么病理生理变化。 确定遗传易感性位点影响 HAND 的病理生理学机制的一种创新方法是检查它们对神经病理学中间表型 (NIP) 的影响。在最基本的层面上，HAND 被认为是一系列生理事件的最终结果，这些生理事件始于 HIV 诱导的细胞变化，并受到遗传因素的影响。在本研究的背景下，我们认为在 HAND 发病机制的因果链开始附近发生的可量化的神经病理学变化是 HAND 行为障碍特征所必需的 NIP。存在许多与 HAND 相关的候选 NIP，包括突触树突简化；巨噬细胞浸润；小胶质细胞和星形胶质细胞激活，以及β-淀粉样蛋白沉积。通过检查来自临床特征良好的队列的脑组织中遗传易感性位点和 NIP 之间的关系，将有可能确定 1) 哪些遗传变异与 HAND 具有生物学相关性，2) 它们发挥作用的病理生理机制神经行为表型的影响，3) NIP 作为 HAND 潜在致病因素的相对重要性。 这项研究与 NIH 阐明导致 HAND 的生理机制的使命高度相关。为了实现我们的目标，我们将使用免疫组织化学和高通量定量程序来表征多个大脑区域的 NIP。我们的目标是确定基因型和重要辅助因素（例如年龄、物质使用、cART 使用）在多大程度上改变这些 NIP。我们的第二个目标是确定遗传易感性位点、NIP 和神经认知障碍之间的线性因果关系。为此，我们将使用网络边缘定向来确定基因型和 NIP 之间的因果关系。这将与结构方程模型相结合，从而创建一个全面的 HAND 通路模型，其中包括基因型、NIP、神经认知功能和重要的辅助因子。