Combinational Systems Analyses to Identify Neural Circuits Perturbed by HIV

描述（由申请人提供）：随着艾滋病毒感染人群的老龄化，有证据表明HAND的累积发病率正在继续增加8-12。目前还不清楚为什么一些感染艾滋病毒的人会出现认知障碍，而另一些人不会。同样，没有生物学指标可以识别无症状神经认知障碍（ANI）的个体，这些个体可能发展为更严重的认知障碍形式，包括轻度神经认知障碍（MND）或坦率性痴呆（HIV相关痴呆；HAD），或者可能自发改善。本建议的目的是使用组合信息学方法来识别在HAND过程中早期受到干扰的神经系统，并确定神经系统的纵向变化如何与认知功能的变化相关。这些综合信息学方法将在HAND的分子理解方面开辟新天地，这将有助于开发新型神经保护药物。这些方法也有可能确定一组独特的替代标记物，这些标记物可以识别处于HAND前驱期的HIV感染者，此时神经保护治疗干预将具有最大的益处。为了实现这些目标，我们建议使用组合信息学系统方法来询问一组独特的临床样本，这些样本已经在多个性能站点进行了广泛的分析。

DESCRIPTION (provided by applicant): As people are now aging with HIV-infection, there is evidence that the cumulative incidence of HAND is continuing to increase 8-12. It is not currently understood why some HIV-infected individuals develop cognitive impairments while others do not. Likewise, there are no biological measures that can identify individuals with asymptomatic neurocognitive impairments (ANI) who are likely to progress to more severe forms of cognitive impairments including mild neurocognitive disorder (MND) or frank dementia (HIV associated dementia; HAD), or who is likely to spontaneously improve. The objective of this proposal is to use combinational informatics approaches to identify neural systems that are perturbed early in the course of HAND, and to determine how longitudinal changes in neural systems are related to changes in cognitive function. These combined informatics approaches will break new ground in the molecular understanding of HAND that will aid in the development new classes of neuroprotective drugs. These approaches are also likely to pinpoint a unique set of surrogate markers that may identify HIV infected individuals at a prodromal phase of HAND, when neuroprotective therapeutic intervention would have the greatest benefit. To accomplish these goals we propose to use a combinational informatics systems approach to interrogate a unique set of clinical samples that have undergone extensive analysis at multiple performance sites.