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

HIV-1转基因大鼠模型中NAD代谢和慢性炎症的机制

• 批准号: 10083681
• 负责人: WALTER ROYAL
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083681
• 关键词: 5' -AMP-activated protein kinase; Alcohols; Animals; Anti-Retroviral Agents; Apoptosis; Astrocytes; Behavioral; Biogenesis; Brain; Carbohydrates; Cells; Chronic; Clinical; Consequences of HIV; Country; Development; Environment; Fatty acid glycerol esters; Gene Expression; Generations; Genes; Glycoside Hydrolases; HIV; HIV Infections; HIV-1; Healthcare; Healthcare Systems; Human; Immune; Immunologic Deficiency Syndromes; Immunologic Markers; Immunologics; In Vitro; Inbred F344 Rats; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Interleukin-1; Maintenance; Mediating; Metabolism; Mitochondria; Modeling; Multiple Abnormalities; Nervous system structure; Neurocognitive Deficit; Neurologic; Neuronal Dysfunction; Nicotinamide adenine dinucleotide; Nude Rats; PPAR gamma; Pathologic; Pharmaceutical Preparations; Plasmids; Production; Protein Kinase; Proteins; Rat Transgene; Rattus; Regulation; Risk; Role; SIRT1 gene; Series; Sirtuins; Symptoms; TNF gene; Testing; Transcription Coactivator; Transgenes; Transgenic Animals; Transgenic Organisms; Translating; United States Department of Veterans Affairs; Veterans; care providers; chemical reaction; cytokine; effective therapy; experience; immune activation; in vivo; in vivo Model; inhibitor/antagonist; innovation; nervous system development; novel strategies; response

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.

退伍军人医疗保健管理局 (VHA) 治疗了超过 26,000 名 HIV 感染者，使其成为 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 HIV 感染，超过 40% 的人面临与 HIV 相关的神经认知障碍的风险 （国家癌症研究所）。因此，大量退伍军人可能会出现与 NCI 相关的症状，总体而言 对抗逆转录病毒药物治疗反应不佳。 NCI 发展的因素包括 由于促炎细胞因子（例如 TNF-α 和 IL-1β）和其他细胞因子的产生增强而导致神经元功能障碍 由大脑中感染艾滋病毒的细胞分泌的炎症介质。 星形胶质细胞在大脑细胞中所占比例最大，当感染 HIV-1 时，星形胶质细胞会分泌 可能对大脑产生重大有害影响的促炎因子。在这个提案中我们 将检查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、能量传感分子 5' AMP 激活蛋白激酶 (AMPK)、过氧化物酶体 增殖剂激活受体 γ 共激活剂 1-α (PGC1α) 和 Sirtuin SIRT1 在抑制神经功能中的作用 由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，是在野生型 F344 Fischer 大鼠（HIV1Tg 大鼠）背景下开发的，另一个是 最近开发的，是在裸费舍尔大鼠（HIV1TgNu+ 大鼠）背景上进行的；它提供了一个模型 在严重免疫缺陷的情况下感染艾滋病毒。 本优点中提出的研究将利用 F344 和 F344 裸 (F344Nu+) 大鼠原代进行 星形胶质细胞转染含有插入物的质粒，该插入物与存在于细胞中的转基因相同 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。 将用 NAD、CD38、AMPK 和 SIRT1 的激活剂和抑制剂处理细胞和动物，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 开发更有效的人类 HIV 相关 NCI 治疗方法。