Oxidative Stress Markers and HIV Dementia

描述(申请人提供)：艾滋病毒痴呆症(HIV-D)是美国年轻人痴呆症最常见的原因之一。中枢神经系统(CMS)内异常的免疫激活和氧化应激在HIV-D的发展中起着重要作用。细胞因子和氧化还原平衡的破坏会产生可攻击蛋白质、脱氧核酸和脂膜的活性氧物种，导致细胞功能障碍和细胞死亡。我们小组的最新数据显示，氧化应激的几个标记物增加，特别是神经酰胺、鞘磷脂和4-羟基壬烯醛(HNE)。该项目将汇集一组患有不同程度神经认知障碍的HIV+患者：1)确定一组接受HAART治疗的受试者中氧化应激标志物与HIV-D之间的联系，并确定这些标志物与巨噬细胞和星形胶质细胞激活的实验室标志物以及炎症和神经元损伤的神经成像标志物之间的关系；2)确定氧化应激标志物是否可预测HIV-D的可逆性或进展；3)确定抗氧化剂治疗、米诺环素对HIV-D患者是否安全、改善HIV相关认知障碍和降低氧化应激标志物。我们提出了第一项大规模前瞻性研究，以量化接受HAART治疗的HIV相关认知障碍患者的氧化应激新标记物。本研究旨在研究这些标记物与炎症和神经元损伤的新型免疫激活和神经影像标记物之间的相互关系，以确定氧化应激在HIV-D发病机制中的作用。这项提议可能会确定艾滋病毒-D治疗的新细胞靶点，我们将启动一项受控临床试验，以测试一种治疗艾滋病毒-D的新药物。我们认为，氧化应激在HIV-D的发展中起着重要作用，减少氧化应激的策略可能成为治疗HIV-D的有用靶点。

DESCRIPTION (provided by applicant): HIV dementia (HIV-D) is one of the most common causes of dementia in young adults in the United States. Aberrant immune activation and oxidative stress within the central nervous system (CMS) play a significant role in the development of HIV-D. Disruptions in cytokine and redox balance produce reactive oxygen species which can attack proteins, deoxynucleic acids, and lipid membranes resulting in cellular dysfunction and cell death. Recent data from our group demonstrate increases in several markers of oxidative stress, specifically, ceramide, sphingomyelin, and 4-hydroxynonenal (HNE). The project will assemble a cohort of HIV+ individuals with varying degrees of neurocognitive impairment: 1) to define the association between markers of oxidative stress and HIV-D in a cohort of HAART-treated subjects and to determine the relationship between these markers and laboratory markers of macrophage and astrocyte activation and neuroimaging markers of inflammation and neuronal injury, 2) to determine whether markers of oxidative stress predict either the reversibility or the progression of HIV-D, and 3) to determine whether the antioxidant treatment, minocycline is safe in patients with HIV-D, improves HIV associated cognitive impairment, and decreases markers of oxidative stress. We propose the first large-scale prospective study to quantify novel markers of oxidative stress in individuals with HIV-associated cognitive impairment receiving HAART. This proposal examines the interrelationship between these markers and novel immune activation and neuroimaging markers of inflammation and neuronal injury to define the role of oxidative stress in the pathogenesis of HIV-D. This proposal will potentially identify new cellular targets of HIV-D treatment, and we will initiate a controlled clinical trial to test a new agent for the treatment of HIV-D. We believe that oxidative stress plays a significant role in the development of HIV-D, and strategies to decrease oxidative stress may serve as a useful therapeutic target to treat HIV-D.