Comparative Study of Molecular Signatures in HIV-Related Neuropathogenesis and Alzheimer's Disease

HIV 相关神经发病机制和阿尔茨海默氏病分子特征的比较研究

• 批准号: 10407966
• 负责人: DOUGLAS R GALASKO
• 金额: $ 79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407966
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Autopsy; Binding; Biological Markers; Blood; Blood specimen; CD4 Positive T Lymphocytes; Caring; Chronic; Clinical; Cognition; Comparative Study; Complex; Control Groups; Data; Diagnosis; Disease; Evaluation; Future; Gene Expression; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Impairment; Individual; Inflammatory; Laboratories; Mass Spectrum Analysis; Measures; Mediation; Metabolic; Modeling; Molecular; Molecular Profiling; Molecular Structure; Nerve Degeneration; Neuraxis; Neurocognition; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neuropathogenesis; Outcome; Oxidative Stress; Parents; Participant; Pathway interactions; Peripheral; Persons; Plasma; Population; Process; Regulatory Pathway; Research; Risk; Sampling; Time; Viral; Visit; aging population; antiretroviral therapy; base; brain tissue; cognitive function; cohort; design; genetic variant; improved; innovation; insight; lipid metabolism; lipidome; lipidomics; metabolome; metabolomics; mild neurocognitive impairment; monocyte; multidimensional data; network models; neurobehavioral; peripheral blood; predictive modeling; programs; protein degradation; tau Proteins; tau-1; transcriptome; transcriptome sequencing; transcriptomics

Abstract Problem. The use of combination antiretroviral therapy (cART) has allowed people living with HIV (PLWH) to live longer and healthier. Nevertheless, more than half of PLWH still have varying degrees of HIV Associated Neurocognitive Disorder (HAND) despite viral suppression with cART. Longer duration of HIV infection and aging may have conjoining negative effects on cognitive function and neurodegeneration. As the PLWH are growing older, it is important to differentiate HAND from neurodegenerative diseases affecting the general aging population, such as Alzheimer's Disease (AD). Both HAND and AD might share neuropathological mechanisms, which have not been systematically studied, in PLWH during suppressive cART. Overarching Goal. To characterize the molecular signatures underlying HAND during viral suppression on cART, and describe the commonalities and differences with those molecular signatures associated with AD. Cohorts and Samples. We will use complementary and well-characterized cohorts with extensive longitudinal available clinical, neurocognitive and laboratory data from two major research programs: HIV Neurobehavioral Research Program (HNRP) and Shiley-Marcos Alzheimer's Disease Research Center (ADRC). A. HNRP: We will retrospectively include CSF and blood samples from participants who (i) had normal cognition at baseline and had incident HAND at a subsequent time-points (HAND group, n=100) and, (ii) age- matched participants who had normal cognition at baseline and did not develop HAND in any of the subsequent time-points (no-HAND group, n=100). For the HAND group, we will also evaluate samples at the time-point when HAND was first diagnosed. For subset of participants (n=20), we will include stored post- mortem brain tissue for exploratory evaluation. B. ADRC: We will retrospectively include CSF and blood samples from participants who: (i) had Mild Neurocognitive Impairment (MCI) at baseline and developed AD in the subsequent time-point (AD group, n=50) and, (ii) age-matched participants who had normal cognition during all observational time-points (control group, n=50). Brain tissue will also be available for a subset of participants (n=20) for exploratory evaluation. Approach. We propose a highly innovative approach by generating and analyzing high dimensional data focused on study objectives designed to be responsive to the parent RFA-AG-18-023. Specifically, we will generate metabolomics and lipidomics (aim 1), transcriptomics (aim 2), and we will integrate these data with relevant AD-associated genetic variants, clinical variables and measures of classical AD biomarkers (aim 3) to develop molecular interaction networks and predictive models of HAND and AD. Our study has the potential to yield highly translatable results by identifying pathways that can be targeted to improve care for both ageing HIV population and AD population. The data collected as part of this project will also lay the groundwork for future studies that can tackle a wide variety of open questions concerning aging, HIV and neurodegeneration.

抽象的 问题。使用抗逆转录病毒疗法（CART）的使用使患有艾滋病毒（PLWH）的人到 寿命更长，更健康。然而，超过一半的PLWH仍然具有不同程度的艾滋病毒 神经认知障碍（手），尽管被推车抑制了病毒。艾滋病毒感染的持续时间更长 衰老可能会导致对认知功能和神经退行性的负面影响。因为PLWH是 越来越老，重要的是将手与影响一般的神经退行性疾病区分开 人口老龄化，例如阿尔茨海默氏病（AD）。手和广告都可以共享神经病理学 在抑制车期间，在PLWH中尚未系统地研究的机制。 总体目标。表征病毒抑制期间手下的分子特征 购物车，并描述与AD相关的分子特征的共同点和差异。 队列和样品。我们将使用辅助和良好的人群和广泛的纵向 来自两个主要研究计划的可用临床，神经认知和实验室数据：HIV神经行为 研究计划（HNRP）和Shiley-Marcos阿尔茨海默氏病研究中心（ADRC）。 A. HNRP：我们将回顾性地包括CSF和来自（i）正常的参与者的血液样本 基线的认知，并在随后的时间点（手组，n = 100）和（ii）年龄 - 匹配基线时具有正常认知的参与者 随后的时间点（无手，n = 100）。对于手组，我们还将评估样本 首次诊断出手的时间点。对于参与者的子集（n = 20），我们将包括存储的后 验证性评估的尸体脑组织。 B. ADRC：我们将回顾性地包括CSF和来自参与者的血液样本：（i）温和 基线时神经认知障碍（MCI）并在随后的时间点开发AD（AD组， n = 50）和（ii）在所有观察时间点（对照）期间具有正常认知的年龄匹配的参与者 组，n = 50）。脑组织也将用于一部分参与者（n = 20）进行探索性评估。 方法。我们通过生成和分析高维数据提出了一种高度创新的方法 专注于研究目标，旨在对父母RFA-AG-18-023做出反应。具体来说，我们会的 生成代谢组学和脂质组学（AIM 1），转录组学（AIM 2），我们将将这些数据与 相关的AD相关遗传变异，临床变量和经典AD生物标志物的测量（AIM 3） 开发分子相互作用网络以及手和AD的预测模型。我们的研究有可能 通过识别可以针对以改善衰老的护理的途径来产生高度翻译的结果 艾滋病毒人群和广告人口。作为该项目一部分收集的数据也将为 未来的研究可以解决有关衰老，艾滋病毒和神经变性的各种开放问题。