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

鉴定与 HIV-1 和甲基苯丙胺相关的中枢神经系统损伤和复原力的生物标志物

• 批准号: 10189544
• 负责人: Jennifer E Iudicello
• 金额: $ 71.55万
• 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: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189544
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Age; Albumins; Area; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Brain; Cardiovascular Diseases; Categories; Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrovascular Circulation; Cholesterol; Clinic; Clinical; Clinical Data; Clinical Research; Clinical assessments; Cohort Studies; Collection; Data; Data Store; Diagnosis; Disease; Early Diagnosis; Early Intervention; Elements; Enrollment; Environment; Feces; Funding; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Host Defense Mechanism; Immune; Inflammation; Intervention; Investments; Lead; Machine Learning; Measures; Metabolic Diseases; Methamphetamine; Methamphetamine dependence; Methods; Modeling; Monitor; National Institute of Drug Abuse; Neuraxis; Neurocognitive; Neurologic; Neuropsychology; Organ; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathology; Performance; Peripheral; Persons; Plant Roots; Predictive Value; Process; Prognosis; ROC Curve; Research; Risk; Risk Factors; Sensitivity and Specificity; Specimen; Spinal Puncture; Standardization; Structure; Systemic disease; Techniques; Time; Translating; Translational Research; Translations; Validation; Vascular Diseases; Visit; adverse outcome; assay development; base; biomarker identification; biomarker panel; biomarker signature; biomarker validation; biosignature; blood-brain barrier permeabilization; central nervous system injury; clinical Diagnosis; clinical translation; clinically relevant; cohort; cost efficient; drug development; drug of abuse; follow up assessment; follow-up; functional decline; functional disability; functional outcomes; gut microbiome; improved; insight; interest; machine learning method; methamphetamine effect; methamphetamine use; neurobehavioral; neuroimaging; neurotoxic; novel; patient oriented research; predictive modeling; primary outcome; programs; public health relevance; random forest; resilience; response; risk prediction model; sex; stool sample; time use; tool

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.

项目概要 甲基苯丙胺 (METH) 经常被滥用，并且是艾滋病毒的危险因素。冰毒也会增加风险 HIV 期间的不良后果，包括 HIV 相关神经认知障碍 (HAND)。多项研究 已经证明了冰毒和艾滋病毒对大脑结构和功能的神经毒性作用，以及 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 将是了解冰毒和艾滋病毒相关发病机制的宝贵工具，并可以提供 对药物开发有价值的见解。冰毒和艾滋病毒对中枢神经系统以外的影响（例如，血管和神经系统） 代谢疾病）也很重要，也是该领域的一个关键空白。该领域的另一个关键空白 是将研究成果转化为临床，包括可用于检测 METH- 和 HIV 相关的中枢神经系统损伤和整个疾病阶段的功能障碍。更鲜为人知的是 宿主防御机制恢复能力的生物标志物。因此，为了响应 RFA-DA-18-023，该项目 提议筛选反映病理学和研究的综合临床和研究生物标志物组 弹性，旨在识别和验证可以改善临床评估的生物特征 以及与冰毒和艾滋病毒相关的大脑和外周并发症的诊断。为了实现这一目标，我们 建议利用 NIDA 之前对 UCSD 资助的转化型甲基苯丙胺艾滋病项目的投资 研究中心 (TMARC)，进行标准化神经行为、神经影像和神经医学研究 对因冰毒使用和艾滋病毒感染而不同的参与者进行评估。我们将回顾并全面 重新评估其中 200 名参与者。神经影像学方法将包括脑血流量、中枢神经系统的测量 代谢水平，以及一种新颖的神经影像学测量来估计血脑屏障（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， 存储之前基线访问的样本以及新访问的样本，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。这种方法将提供独特的纵向数据，以便识别 预测中枢神经系统损伤和恢复能力变化的生物特征。我们将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 HIV 中心接受过评估 神经行为研究计划以及拥有全面数据和存储样本（例如脑脊液）的人 可用的。为了更好地响应 RFA 的临床转化目标，我们还将比较测量的结果 生物标志物与常规临床评估期间获得的数据相结合，目的是识别临床 METH 和 HIV 相关中枢神经系统损伤的生物特征。全面了解冰毒和艾滋病毒的影响 系统和中枢神经系统流程的研究将解决该领域的关键差距。这一见解还应告知 开发检测方法以告知诊断以及有效的疾病和治疗监测。