CSF Molecular Marker Study Consortium

本申请提出建立一个国际性的多中心联合体，其地点位于瑞典哥德堡、意大利米兰、美国旧金山弗朗西斯科和澳大利亚悉尼，以促进脑脊液（CSF）分子标记物的合理使用，从而管理（预防、诊断和治疗）和了解HIV-1脑感染的发病机制及其主要临床后果，AIDS痴呆综合征（ADC）。申请的资金将用于：1。发展合作财团的基础设施、方法和程序，以便于采用一种顺序的、更迅速的方法来分析HIV感染中CSF的变化，这种方法可以由一个单一的机构完成; 2.进行候选CSF标志物的初步组的初始筛选，其中组分评估病毒学、宿主免疫学、神经和血脑屏障对CSF组成的贡献，并使用约160个明确定义的横截面CSF和血液样品对的矩阵将其减少到较小的初始核心CSF标志物组; 3.通过额外的（a）横断面研究，以测试单个和组合标志物的诊断价值，以及（B）开始停止抗逆转录病毒治疗后标志物动态的短期纵向研究，进一步评估并将该组合改进为充分表征的次级核心CSF标志物组合; 4.继续扩大以扩大CSF/血浆样本储存库，并评估作为候选物的其他标记物，以添加或替换二次电池的组分标记物，并解决发病机制问题; 5.开发个体标记动态及其相互作用的正式模型; 6.利用这些研究的信息制定一套临床试验设计的CSF标志物指南。此外，在本研究的整个5年期间，将采取措施准备并随后通过与使用其他模式的研究（包括功能性神经影像学和遗传分析）整合来扩展本研究。

This application proposes to establish an international, multi-centered consortium with sites in Goteborg Sweden, Milan Italy, San Francisco USA, and Sydney Australia to advance the rational use of cerebrospinal fluid (CSF) molecular markers to manage (prevent, diagnose and treat) and understand the pathogenesis of HIV-1 brain infection and its major clinical consequence, the AIDS dementia complex (ADC). The requested funding will be used to: 1. Develop the infrastructure, methodologies and procedures of the cooperative consortium that facilitate a sequential, more expeditious approach to analysis of CSF changes in HIV infection that could be accomplished by a single institution; 2. Carry out initial screening of a preliminary group of candidate CSF markers, with components assessing virological, host immunological, neural and blood-brain barrier contributions to CSF composition, and to reduce this to a smaller initial core CSF marker battery using a matrix of about 160 well-defined, cross-sectional CSF and blood sample pairs; 3. Further assess and refine this battery into a well-characterized secondary core CSF marker battery by additional (a) cross-sectional study to test the diagnostic value of the individual and combined markers with a more complex, real-world spectrum of samples and patients and (b) short-term longitudinal studies of marker dynamics after initiation of cessation of anti-retroviral therapy; 4. Continue to enlarge to enlarge CSF/plasma sample repositories and to assess additional markers as candidates to add to or replace component markers of the secondary battery and to address questions of pathogenesis; 5. Develop formal models of individual marker dynamics and their interactions; 6. Use the information derived from these studies to formulate a set of CSF marker guidelines for the design of clinical trials. Additionally, throughout the 5 years of this study, measures will be taken to prepare for and subsequently extend this study through integration with studies using other modalities, including functional neuroimaging and genetic analyses.