Mechanisms of NAD Metabolism and Chronic Inflammation in HIV-1 Transgenic Rat Models

退伍军人医疗管理局(VHA)治疗了超过2.6万名艾滋病毒感染者，使其 美国最大的艾滋病毒感染者护理机构。神经系统并发症通常发生在 艾滋病毒感染，超过40%的人有患艾滋病毒相关神经认知障碍的风险 (NCI)。因此，很可能大量退伍军人经历了与NCI相关的症状，总体上 对抗逆转录病毒药物治疗的反应很差。NCI发展的基础因素包括 促炎症细胞因子(如肿瘤坏死因子-和白介素1-)的产生增加所致的神经元功能障碍 由大脑中感染艾滋病毒的细胞分泌的炎症介质。 星形胶质细胞占大脑细胞的最大比例，当感染HIV-1时，星形胶质细胞分泌 可能对大脑产生重大有害影响的促炎因子。在这份提案中，我们 将研究烟酰胺腺嘌呤二核苷酸(NAD)代谢和激活的潜在影响 糖水解酶CD38，能量敏感分子5‘AMP激活的蛋白激酶(AMPK)，过氧化物酶体 增殖因子激活受体-γ共激活因子1-αα及其sirtuin sirt1在神经抑制中的作用 感染和激活介导的系统炎症和其他神经病理异常 星形胶质细胞。在这些研究中，我们将使用两种HIV-1感染的转基因大鼠模型。一口是井- 建立模型，建立在野生型F344 Fischer大鼠背景上(HIV1Tg大鼠)和另一只， 最近开发的，是基于裸鼠的Fisher背景(HIV1TgNu+鼠)；这提供了一个模型 在存在严重免疫缺陷的情况下感染艾滋病毒的风险。 本研究将利用F344和F344裸鼠(F344Nu+)原代进行研究 将含有与转基因完全相同的插入片段的质粒导入星形胶质细胞 转基因大鼠以及来自大鼠的原代细胞。研究也将在活体内进行，使用动物。 细胞和动物将被NAD、CD38、AMPK和SIRT1的激活剂和抑制剂处理以确定 这些药物对炎症反应和可能发生的神经病理异常的影响。我们 预计利用这些创新模型和方法获得的信息将导致 开发更有效的治疗人类艾滋病毒相关非传染性疾病的方法。

The Veterans Healthcare Administration (VHA) treats more than 26,000 individuals with HIV infection, making it the largest provider of care to HIV-infected individuals in the U.S. Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for developing HIV-related neurocognitive impairment (NCI). Therefore, it is likely that a large number of Veterans experience symptoms related to NCI, which overall responds poorly to treatment with antiretroviral drugs. Factors that underlie the development of NCI include neuronal dysfunction due to enhanced production of proinflammatory cytokines (e.g., TNF- and IL-1) and other inflammatory mediators that are secreted by HIV-infected cells in the brain. Astrocytes make up the largest percentage of cells in the brain and, when infected by HIV-1, secrete proinflammatory factors that can potentially have significant detrimental effects on the brain. In this proposal we will examine the potential effects of nicotinamide adenine dinucleotide (NAD) metabolism and activation of the glycohydrolase CD38, the energy sensing molecule 5' AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and the sirtuin SIRT1 in suppressing nervous system inflammation and other neuropathological abnormalities mediated by infection and activation of astrocytes. For these studies we will utilize two transgenic rat models of HIV-1 infection. One is a well- established model, developed on a wild-type F344 Fischer rat background (the HIV1Tg rat) and the other, developed more recently, is on a on a nude Fisher rat background (the HIV1TgNu+ rat); which provides a model of HIV infection in the presence of severe immunodeficiency. The studies proposed in this Merit will be performed utilizing F344 and F344 nude (F344Nu+) rat primary astrocytes transfected with a plasmid containing an insert that is identical to transgene that is present in the transgenic rats as well as primary cells from the rats. Studies will be also performed in vivo using the animals. The cells and animals will be treated with activators and inhibitors of NAD, CD38, AMPK and SIRT1 to determine the effects of the agents on inflammatory response and neuropathological abnormalities that can occur. We anticipate that information obtained utilizing these innovative models and approaches will lead to the development of more effective treatments for HIV-related NCI in humans.