BIOMARKERS

这是Letendre修改后的项目申请。该项目将通过使用体内生物标记物作为神经发病的细胞和分子机制的窗口，使用翻译方法来了解冰毒、艾滋病毒和丙型肝炎病毒对大脑的影响。我们将检查六类生物标记物(星形胶质细胞、炎症、氧化、营养、神经元和病毒)，它们对应于我们概念模型中概述的主要致病机制。具体目标将是确定与冰毒、艾滋病毒和丙型肝炎相关的不同生物标志物特征；确定冰毒和艾滋病毒与两组特定生物标志物-成纤维细胞生长因子(FGFs)和干扰素诱导蛋白-之间的关系；以及确定生物标志物特征与正在研究的脑损伤的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，大脑区域激活改变，以及谷氨酰胺-谷氨酸循环的变化。为了实现这些目标，我们将检测来自三个风险组的425名参与者脑脊液中的生物标记物浓度。我们还将检测在Heaton项目第二项研究中登记的Meth+个体对聚乙二醇-α-干扰素/利巴韦林治疗丙型肝炎病毒感染的反应中生物标志物分布和脑脊液中干扰素-α浓度的变化。为了更具体地确定近期戒毒与长期戒毒对生物标志物特征的影响，将专门为该项目招募50名在10天内使用过冰毒的吸毒者。这些实验具有创新性，因为它们将确定冰毒、艾滋病毒和丙型肝炎的独特生物标记物特征；在同一标本中测量反映多种损伤机制的脑脊液标记物；调查最近公认的损伤机制，如FGFs；将体内和体外的研究结果联系起来；以及确定聚乙二醇化干扰素-α和利巴韦林对推测的神经发病体内标记物的影响。

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.