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

退伍军人医疗保健管理局（VHA）治疗了26,000多名艾滋病毒感染者， 美国最大的艾滋病毒感染者护理提供者。神经系统并发症通常发生在 艾滋病毒感染，超过40%的人有发展艾滋病毒相关神经认知障碍的风险 （NCI）。因此，很可能有大量的退伍军人经历与NCI相关的症状， 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 由于促炎细胞因子的产生增加而引起的神经元功能障碍（例如，TNF-α和IL-1 β）和其他 炎症介质是由大脑中的HIV感染细胞分泌的。 星形胶质细胞占大脑细胞的最大比例，当被HIV-1感染时， 促炎因子可能对大脑产生显著的有害影响。在本提案中，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CD 38、能量敏感分子5'AMP-活化蛋白激酶（AMPK）、过氧化物酶体 增殖物激活受体γ共激活因子1 α（PGC 1 α）和sirtuin SIRT 1在抑制神经元凋亡中的作用 系统炎症和其他神经病理异常介导的感染和激活 星形胶质细胞对于这些研究，我们将利用两种HIV-1感染的转基因大鼠模型。一个是井- 建立的模型，在野生型F344 Fischer大鼠背景（HIV 1 Tg大鼠）上开发， 最近开发的，是在裸Fisher大鼠背景下（HIV 1 TgNu+大鼠）;这提供了一个模型， 在严重免疫缺陷的情况下感染艾滋病毒。 本Merit中拟定的研究将使用F344和F344裸（F344 Nu+）大鼠进行原代 用含有与存在于星形胶质细胞中的转基因相同的插入物的质粒转染星形胶质细胞。 转基因大鼠以及来自大鼠的原代细胞。还将使用动物进行体内研究。 细胞和动物将用NAD、CD 38、AMPK和SIRT 1的激活剂和抑制剂处理，以确定 药物对可能发生的炎症反应和神经病理学异常的影响。我们 预计利用这些创新模型和方法获得的信息将导致 为人类HIV相关NCI开发更有效的治疗方法。

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.