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: 8411068
• 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/8411068
• 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. PUBLIC HEALTH RELEVANCE: The impact of HIV-associated neurocognitive disorders (HAND) is substantial, affecting upwards of 50% of HIV-infected individuals; therefore, elucidating the neuropathogenesis of this disorder and identifying pharmaceutical targets will improve quality of life for tens of thousands within th United States alone. In recent years, a small number of genetic susceptibility loci have been identified that increase risk for HAND, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis; however, nothing is known of what pathophysiological changes these genetic variants cause. Delineating this relationship will help to clarify the molecular and physiological pathways involved in HAND neuropathogenesis, and this will lead to identification of potential pharmaceutical targets.

描述（由申请人提供）： 尽管广泛使用抗逆转录病毒疗法（CART），但与HIV相关的神经认知障碍（手）的患病率接近50％。手是一种基于从轻度神经认知缺陷到令人衰弱的痴呆症的神经认知障碍的临床诊断。手是宿主免疫激活促进的慢性神经炎症状态的结果。但是，涉及的关键病理生理途径尚不清楚。近年来，已经确定了少数宿主遗传易感性基因座增加手动或影响其前进的风险，这表明其基因产物的生理途径扰动与手动发病机理有关。但是，所有与手动相关的遗传易感性基因座的研究都完全依赖于临床结果。这些遗传变异引起的病理生理变化尚无了解。 一种创新的方法，用于确定遗传易感性基因座影响手的病理生理机制是检查其对神经病理学中间表型或NIP的影响。从最基本的角度来看，手认为手是一系列生理事件的最终结果，这些事件始于HIV诱导的细胞变化，这些变化被遗传因素改变。在本研究的背景下，我们认为该因果关系链的开始是手动发病机理的开始，这是手动障碍特征所必需的NIP。存在许多与手相关的候选nip，包括突触跨性的简化；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。通过检查临床特征良好的队列中的遗传易感性基因座和NIP之间的关系，可能是t确定1）哪些遗传变异与手在生物学上与手相关，2）病理生理机制，通过这些变异，它们对它们对Neurobehavior现象的效应对NIPS的相对效果不足，并将其对NIPS的相对性造成效果。 这项研究与NIH的使命高度相关，以阐明导致手的生理机制。为了实现我们的目标，我们将使用免疫组织化学和高吞吐量定量程序来表征多个大脑区域的NIP。我们的目的是确定基因型和重要的共同因素（例如，年龄，使用物质，使用购物车）在多大程度上修改了这些NIP。我们的第二个目标将确定遗传易感性基因座，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取向来确定基因型和NIP之间的因果关系。这将与结构方程建模集成在一起，从而允许创建包括基因型，NIP，神经认知功能和重要共同因素的全面途径模型。 公共卫生相关性： 与HIV相关的神经认知障碍（手）的影响很大，影响了50％的HIV感染者；因此，阐明这种疾病的神经病发生并确定药物靶标将改善仅美国在美国境内成千上万的生活质量。近年来，已经确定了少数遗传敏感性基因座增加了手的风险，这表明其基因产物与其基因所参与的生理途径的扰动会导致手动发病机理。但是，这些遗传变异引起的病理生理变化尚无了解。描述这种关系将有助于阐明与手神经病发生有关的分子和生理途径，这将导致鉴定潜在的药物靶标。