Identification of Biomarkers of CNS injury and resilience related to HIV-1 and Methamphetamine

项目摘要 甲基苯丙胺（METH）是一种常见的滥用药物，是艾滋病毒的一个危险因素。甲基苯丙胺也会增加 HIV治疗期间的不良后果，包括HIV相关的神经认知障碍（HAND）。多项研究 已经证明了METH和HIV对大脑结构和功能的神经毒性作用， 神经行为和功能表现。中枢神经系统（CNS）损伤和恢复力的生物标志物 将是了解METH和HIV相关发病机制的有价值的工具， 对药物开发有价值的见解。METH和HIV在CNS外的作用（例如，血管和 代谢疾病）也是需要考虑的重要因素，并且是该领域的关键空白。该领域的另一个关键差距是 是将研究结果转化为临床，包括可用于检测METH的生物标志物， HIV相关的CNS损伤和不同疾病阶段的功能损害。更少有人知道 宿主防御机制恢复力的生物标志物。因此，为了响应RFA-DA-18-023，本项目 建议筛选一组反映病理学的临床和研究生物标志物， 弹性，目标是识别和验证可能改善临床评估的生物特征 以及与METH和HIV相关的脑和外周并发症的诊断。为了做到这一点，我们 建议利用NIDA对UCSD的NIDA资助的转化甲基苯丙胺艾滋病的先前投资 研究中心（TMARC），进行标准化的神经行为，神经影像学和神经医学 对不同METH使用和HIV感染的参与者进行评估。我们将全面回顾 重新评估200名参与者。神经影像学方法将包括测量脑血流量、CNS 代谢物水平，和一种新的神经影像学措施，以估计血脑屏障（BBB）的完整性。我们 将测量血液、脑脊液（CSF）和粪便样本中的综合生物标志物组， 从他们之前的基线访视（已储存）和新访视中采集样本，然后分析数据 使用传统的统计方法以及植根于机器学习和因果关系的新技术， 推理建模这一方法将提供独特的纵向数据， 预测CNS损伤和恢复力变化的生物特征。我们会验证观察到的生物特征 在一个由100名参与者组成的独立队列中，这些参与者之前曾在UCSD的艾滋病毒评估中接受过评估， 神经行为研究计划和谁拥有全面的数据和存储标本（例如，CSF） available.为了更好地响应RFA的临床转换目标，我们还将比较测量的 生物标志物与常规临床评估期间获得的数据相比较，目的是鉴定临床 METH和HIV相关CNS损伤的生物特征。深入了解METH和HIV的影响 关于系统性和中枢神经系统进程的报告将解决这一领域的关键差距。这种见解也应该告知 开发检测方法，为诊断和有效的疾病和治疗监测提供信息。

PROJECT SUMMARY Methamphetamine (METH) is commonly abused and is a risk factor for HIV. METH also increases risk for adverse outcomes during HIV, including HIV-associated neurocognitive disorder (HAND). Multiple studies have demonstrated the neurotoxic effects of METH and HIV on brain structure and function, as well as neurobehavioral and functional performance. Biomarkers of central nervous system (CNS) injury and resilience would be valuable tools for understanding the METH- and HIV-associated pathogenesis and could provide valuable insights for drug development. The effects of METH and HIV outside the CNS (e.g., vascular and metabolic disease) are also important to consider and are a key gap in the field. Another key gap in the field is the translation of research findings to the clinic, including biomarkers that may be used to detect METH- and HIV-associated CNS injury and functional impairment across disease stages. Even less is known about biomarkers of resilience of the host defense mechanisms. Thus, in response to RFA-DA-18-023, this project proposes to screen a comprehensive panel of clinical and research biomarkers reflective of pathology and resilience with the goal of identifying and validating biosignatures that may improve the clinical assessment and diagnosis of brain and peripheral complications associated with METH and HIV. To accomplish this, we propose to leverage NIDA’s prior investment in UCSD’s NIDA-funded Translational Methamphetamine AIDS Research Center (TMARC), which performed standardized neurobehavioral, neuroimaging, and neuromedical assessments of participants who differed by METH use and HIV infection. We will recall and comprehensively re-assess 200 of these participants. Neuroimaging methods will include measures of cerebral blood flow, CNS metabolite levels, and a novel neuroimaging measure to estimate integrity of the blood-brain barrier (BBB). We will measure a comprehensive biomarker panel in blood, cerebrospinal fluid (CSF), and stool samples, in specimens from their prior baseline visit, which are stored, and from their new visit and then analyze the data using traditional statistical approaches as well as novel techniques rooted in machine-learning and causal inference modeling. This approach will provide unique longitudinal data that will allow for the identification of biosignatures that predict changes in CNS injury and resilience. We will validate the observed biosignatures in an independent cohort of 100 participants who have been previously assessed at UCSD’s HIV Neurobehavioral Research Program and who have comprehensive data and stored specimens (e.g., CSF) available. To better respond to the clinical translation objective of the RFA, we will also compare measured biomarkers to data that are obtained during routine clinic assessments with the goal of identifying a clinical biosignature of METH- and HIV-related CNS injury. A thorough understanding of the impact of METH and HIV on systemic and CNS processes will address key gaps in the field. This insight should also inform the development of assays to inform diagnosis and effective disease and treatment monitoring.