Macrophage Protein Fingerprints in HIV-1 Dementia

描述（由申请方提供）：单核吞噬细胞（MP;血管周围巨噬细胞和小胶质细胞）的神经毒性分泌产物在HIV-1相关痴呆（HAD）的神经发病机制中起关键作用。因此，我们认为，病毒感染和免疫激活的巨噬细胞的蛋白质组可以用来解开潜在的分子标记或疾病的指纹。当与其他疾病相关蛋白结合时，这些标记物可以预测HAD的发作、进展和对治疗的反应。总之，缺乏生物标志物作为HIV-1感染中认知功能障碍的预测因子对于衡量治疗反应是及时和重要的。我们的目标是利用这一基础设施开发一系列在实验室检测中发现的“新”生物标志物，并反映人类宿主中发生的HIV-1感染和免疫激活。然后，我们将测试假设，血清和脑脊液（CSF）将包含一系列MP激活标志物（或指纹），可以预测HAD。该提案的优势在于其技术创新，方法，跨学科的研究小组，强大的研究环境和蛋白质组学的成功记录。 目标1.鉴定HIV-1感染和免疫活性人单核细胞源性巨噬细胞（MDM）的分泌蛋白组（分泌蛋白谱）。在这一目标的工作反映了这样一种假设，即HIV-1相关痴呆（HAD）的标志物在很大程度上来自脑单核吞噬细胞（MP;血管周围巨噬细胞和小胶质细胞）激活和病毒感染的产物。 目标2.确定HIV-1感染伴认知功能障碍或有认知功能障碍风险的患者血清和脑脊液的蛋白质指纹图谱。该目标的长期目标是发现HAD特异性生物标志物，并观察它们是否基于目标1中所示的免疫活性病毒感染的MDM的产物。

DESCRIPTION (provided by applicant): Neurotoxic secretory products from mononuclear phagocytes (MP; perivascular macrophages and microglia) play a pivotal role in the neuropathogenesis of HIV-1-associated dementia (HAD). Thus, we posit that the proteome of virus-infected and immune activated macrophages could be harnessed to unravel potential molecular markers or fingerprints of disease. Such markers, when combined with other disease associated proteins, could predict the onset, progression and response to therapy for HAD. All together the lack of biomarkers as predictors of cognitive dysfunction in HIV-1 infection is timely and significant for gauging treatment responses. Our goal is to use this infrastructure to develop a "new" series of biomarkers found in laboratory assays and reflective of HIV-1 infection and immune activation as it occurs in the human host. We will then test the hypothesis that serum and cerebrospinal fluid (CSF) will contain a spectrum of MP activation markers (or fingerprints) that can predict HAD. The strengths of this proposal lies in its technical innovation, its approach, the interdisciplinary group of investigators, the strong research environment and a proven successful track record in proteomics. Aim 1. To identify the secretome (profile of secreted proteins) of HIV-1 infected and immune competent human monocyte-derived macrophages (MDM). The work in this aim reflects the hypothesis that markers of HIV-1 associated dementia (HAD) derive, in significant measure, from products of brain mononuclear phagocyte (MP; perivascular macrophage and microglial) activation and viral infection. Aim 2. To determine protein fingerprints (proteome profiles) of serum and CSF of HIV-1 infected patients with or at risk for cognitive impairment. The long-term goal of this aim is to uncover biomarkers specific for HAD and to see if they are based on products of immune competent virus-infected MDM as demonstrated in aim 1.