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: 10341091
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341091
• 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; 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26,000多名艾滋病毒感染的人 美国神经系统并发症的最大护理提供商通常发生在 艾滋病毒感染，超过40％的人有发展与HIV相关的神经认知障碍的风险 （NCI）。因此，大量退伍军人可能会出现与NCI有关的症状，总体而言 对使用抗逆转录病毒药物治疗的反应不佳。 NCI发展的基础的因素包括 由于促炎细胞因子（例如TNF-和IL-1）的产生增强而引起的神经元功能障碍以及其他 由大脑中的HIV感染细胞分泌的炎症介质。 星形胶质细胞构成大脑中最大的细胞，当被HIV-1感染时， 可能对大脑产生重大有害影响的促炎性因素。在这个建议中，我们 将检查烟酰胺腺嘌呤二核苷酸（NAD）代谢的潜在影响和激活 GlyCohOlolase CD38，能量传感分子5'AMP激活的蛋白激酶（AMPK），过氧化物组 在抑制神经中，增生剂激活的受体伽马共振剂1-α（PGC1α）和sirtuin sirt1 系统感染和其他通过感染和激活介导的神经病理异常 星形胶质细胞。对于这些研究，我们将利用HIV-1感染的两个转基因大鼠模型。一个人是一个很好的 建立的模型，在野生型F344 Fischer大鼠背景（HIV1TG大鼠）和另一个上开发的模型 最近开发的是裸体的Fisher大鼠背景（HIV1TGNU+大鼠）；提供模型 在严重免疫缺陷存在下HIV感染的。 该优点提出的研究将使用F344和F344裸（F344NU+）大鼠主要进行 星形胶质细胞用质粒翻译，该质粒包含插入物，该插入物与在 转基因大鼠以及大鼠的原代细胞。研究还将在体内使用动物进行。 细胞和动物将用NAD，CD38，AMPK和SIRT1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异常的影响。我们 预计使用这些创新模型和方法获得的信息将导致 开发针对人类HIV相关的NCI的更有效的治疗方法。