CSF Molecular Marker Study Consortium

这项申请建议建立一个国际性的多中心联盟，在瑞典哥德堡、意大利米兰、美国旧金山和澳大利亚悉尼设有办事处，以促进合理使用脑脊液(CSF)分子标记物来管理(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--艾滋病痴呆综合征(ADC)。所申请的资金将用于：1.发展合作联合体的基础设施、方法和程序，以促进采用顺序、更快速的办法分析可由单一机构完成的脑脊液感染的脑脊液变化；2.对初步候选脑脊液标记物进行初步筛选，其组成部分评估病毒学、宿主免疫学、神经和血脑屏障对脑脊液成分的贡献，并利用约160对明确的横截面脑脊液和血液样本对的矩阵，将其缩减为较小的初始核心脑脊液标记物组合；3.通过额外的(A)横断面研究，用更复杂的、真实的样本和患者谱来测试单个和联合标志物的诊断价值，以及(B)在开始抗逆转录病毒治疗后对标志物动力学进行短期纵向研究；4.继续扩大扩大脑脊液/血浆样本储存库，并评估额外的标志物，作为添加或替换次级细胞系的组成部分标志物的候选者，并解决发病机制问题；5.发展个体标志物动力学及其相互作用的正式模型；6.使用从这些研究中获得的信息来制定一套用于临床试验设计的脑脊液标记物指南。此外，在这项研究的5年中，将采取措施准备这项研究，并随后通过与其他方式的研究相结合来扩展这项研究，包括功能神经成像和遗传分析。

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.