BIOMARKERS

这是一个由Letendre项目修改后的应用程序。该项目将使用一种翻译方法，通过使用体内生物标志物作为神经发病机制的细胞和分子机制的窗口，来了解METH，HIV和HCV对大脑的影响。我们将研究六类生物标志物（星形胶质细胞，炎症，氧化，营养，神经元和病毒），这对应于我们的概念模型中概述的主要致病机制。具体的目标将是确定与METH、HIV和HCV相关的不同生物标志物谱;确定METH和HIV与两组特定生物标志物、成纤维细胞生长因子（FGF）和干扰素诱导蛋白之间的关系;并确定生物标志物谱与正在研究的脑损伤关键指标之间的关系。 其他项目，包括神经认知障碍，运动障碍，改变局部脑激活，和谷氨酰胺-谷氨酸循环的变化。为了实现这些目标，我们将检查入组本计划的三个风险组的425名参与者的CSF中的生物标志物浓度。我们还将检查入组希顿项目研究2的METH+个体中干扰素（IFN）-α生物标志物谱和CSF浓度对PEG-IFN-α/利巴韦林治疗HCV感染的反应变化。为了更具体地确定近期与长期戒断METH对生物标志物特征的影响，本项目将专门招募10天内使用过METH的50名使用者。这些实验具有创新性，因为它们将确定METH、HIV和HCV的独特生物标志物特征;测量反映相同标本中多种损伤机制的CSF标志物;研究最近公认的损伤机制，如FGF;将体内和体外结果联系起来;并确定PEG-IFN-α和利巴韦林对推定的体内神经发病机制标志物的影响。

This is a revised application for Project by Letendre. This Project will use a translational approach to understand the effects of METH, HIV, and HCV on the brain by using in vivo biomarkers as windows into cellular and molecular mechanisms of neuropathogenesis. We will examine six categories of biomarkers (astroglial, inflammatory, oxidative, trophic, neuronal, and viral), which correspond to the major pathogenic mechanisms outlined in our conceptual model. The specific aims will be to identify distinct biomarker profiles that are associated with METH, HIV, and HCV; to identify the relationships between METH and HIV and two specific groups of biomarkers, fibroblast growth factors (FGFs) and interferon-inducible proteins; and to determine the relationships between biomarker profiles and key indicators of brain injury being studied in other Projects, including neurocognitive impairment, movement disorders, altered regional brain activation, and changes in glutamine-glutamate cycling. To accomplish these aims, we will examine biomarker concentrations in CSF from 425 participants from the three risk groups enrolled into this Program. We will also examine changes in biomarker profiles and CSF concentrations of interferon (IFN)-alpha in response to PEG-IFN-alpha/ribavirin treatment of HCV infection in METH+ individuals enrolled in Study 2 of Project by Heaton. In order to more specifically determine the effects of recent versus long-term abstinence from METH on biomarker profiles, an added group of 50 METH users who have used within 10 days will be enrolled specifically for this Project. These experiments are innovative because they will determine the unique biomarker signatures of METH, HIV, and HCV; measure CSF markers reflecting multiple mechanisms of injury in the same specimens; investigate recently recognized mechanisms of injury, such as FGFs; link in vivo and in vitro findings; and determine the effects of PEG-IFN-alpha and ribavirin on putative in vivo markers of neuropathogenesis.