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

基本信息

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
项目类别：
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

项目摘要

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，它是感染艾滋病毒的一个危险因素，也会增加感染艾滋病毒的风险。 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，以及中枢神经系统（CNS）损伤和恢复能力的神经行为和功能表现。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。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各个疾病阶段的功能障碍知之甚少。因此，为了响应 RFA-DA-18-023，该项目。建议筛选反映病理学和研究情况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 NIDA 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我们将回顾并全面评估对冰毒使用和艾滋病毒感染情况不同的参与者的评估。重新评估其中 200 名参与者的神经影像方法将包括脑血流、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。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）的人为了更好地响应 RFA 的临床翻译目标，我们还将比较测量结果。生物标志物到常规临床评估期间获得的数据，目的是确定临床评估冰毒和艾滋病毒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。关于系统和 CNS 流程的研究将解决该领域的关键差距。开发检测方法以告知诊断以及有效的疾病和治疗监测。