Chronic Alcohol Dysregulation of Anabolic Signaling in Skeletal Muscle of SIV-Infected Rhesus Macaques

感染 SIV 的恒河猴骨骼肌合成代谢信号的慢性酒精失调

• 批准号: 8983481
• 负责人: Stephen Michael Ford
• 金额: $ 3.41万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8983481
• 关键词: 1-Phosphatidylinositol 3-Kinase; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adipose tissue; Adult; Alcohol abuse; Alcohols; Animal Model; Animals; Anti-Retroviral Agents; Behavior; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Disease; Complement; Critical Thinking; Data; Deposition; Development; Disease Progression; Ensure; Environment; Fellowship; Funding; Future; General Population; Glucose; Glycogen; HIV; HIV Infections; Health Sciences; High Prevalence; Impairment; In Vitro; Individual; Inflammatory; Insulin; Insulin Resistance; Leadership; Life; Life Expectancy; Lifestyle Therapy; Lipodystrophy; Literature; Louisiana; Macaca; Macaca mulatta; Mediating; Mentors; Mentorship; Metabolic; Metabolic syndrome; Molecular; National Institute on Alcohol Abuse and Alcoholism; National Research Service Awards; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Physiology; Prevalence; Regimen; Reporting; Research; Research Personnel; Resources; SIV; Sampling; Scientist; Signal Transduction; Site; Skeletal Muscle; Sucrose; Techniques; Testing; Tissues; Training; Training Programs; Universities; Up-Regulation; Virus Diseases; Writing; abdominal fat; adiponectin; alcohol research; alcohol use disorder; base; binge drinking; blood glucose regulation; chronic alcohol ingestion; disorder prevention; end stage disease; experience; glucose uptake; in vivo; indexing; insight; insulin signaling; intravenous glucose tolerance test; male; mortality; oral communication; protein tyrosine phosphatase 1B; public health relevance; response; skills; success; therapeutic target; translational study

 DESCRIPTION (provided by applicant): Alcohol is the most frequently abused drug in the US, and approximately 30% of US adult residents have an alcohol use disorder (AUD) during their lives. According to a recent CDC report, the prevalence of HIV infection in the US is 1.15 million individuals. The prevalence of AUD in HIV patients is greater than the prevalence of AUD in the general population. Effective anti-retroviral therapy (ART) has significantly decreased HIV patients' progression to AIDS and has increased the life expectancy of persons living with HIV/AIDS (PLWHA); however, prolonged survival has been associated with metabolic disturbances, including lipodystrophy, insulin resistance, and metabolic syndrome. Chronic alcohol consumption has also been shown to contribute to the development of insulin resistance and lipodystrophy. To our knowledge, there have been no previous studies to investigate the impact of both CBA administration and HIV/SIV on insulin signaling. Our studies, using male rhesus macaques that are chronically administered binge alcohol (CBA) or isocaloric sucrose (SUC), have revealed that CBA administration potentiates a pro-inflammatory and pro-oxidative skeletal muscle milieu and decreases phosphatidylinositol-3-kinase (PI3K) activity and results in upregulation of protein tyrosine phosphatase 1B (PTP1B) expression in skeletal muscle at the end stage of the disease. More recent studies have revealed that CBA significantly increases abdominal fat deposition and significantly decreases circulating adiponectin levels at 11 months post-SIV infection. Furthermore, frequently sampled intravenous glucose tolerance tests in these animals show that at 11 months post-SIV, CBA macaques have a significant decrease in disposition index suggesting impaired insulin responses at target tissues, including skeletal muscle. Reports in the scientific literature and our preliminary data support the central hypothesis that CBA decreases insulin- mediated anabolic responses in skeletal muscle of SIV-infected macaques. The proposed studies to be performed as part of the training plan of the applicant will use an integrated approach to assess the following Specific Aims: 1) To test the prediction that CBA decreases insulin-mediated glucose uptake and glycogen synthesis in skeletal muscle of SIV-infected macaques and 2) To identify the site(s) of insulin signaling cascade disruption in skeletal muscle of SIV-infected macaques following CBA administration. Findings from the proposed studies will provide evidence to elucidate the underlying molecular derangements in skeletal muscle insulin signaling following combination of CBA and SIV/ART and may offer insight into therapeutic targets aimed at ameliorating metabolic dysregulation in persons living with HIV/AIDS.

 描述（由适用提供）：酒精是美国最常见的滥用药物，大约30％的美国成年居民在他们的一生中患有酒精使用障碍（AUD）。根据最近的一份CDC报告，美国艾滋病毒感染的患病率是115万人。 HIV患者AUD的患病率大于普通人群中AUD的患病率。有效的抗逆转录病毒疗法（ART）显着改善了艾滋病毒患者对艾滋病的发展，并提高了艾滋病毒/艾滋病患者的预期寿命（PLWHA）；然而，长期生存与代谢灾害有关，包括脂肪营养不良，胰岛素抵抗和代谢综合征。慢性饮酒也已被证明有助于胰岛素抵抗和脂肪营养不良的发展。据我们所知，我们以前没有研究研究CBA给药和HIV/SIV对胰岛素信号的影响。 Our studies, using male rhesus macaques that are chronically administered Binge Alcohol (CBA) or isocaloric sucrose (SUC), have revealed that CBA administration potentials a pro-inflammatory and pro-oxidative skeletal muscle milieu and decreases phosphatidylinositol-3-kinase (PI3K) activity and results in upregulation of protein tyrosine phosphatase 1B (PTP1B)在疾病结束时骨骼肌的表达。最近的研究表明，CBA显着增加了腹部脂肪沉积，并在SIV后11个月时显着降低了循环的脂联素水平。此外，这些动物中经常采样的静脉葡萄糖耐受性测试表明，在SIV后11个月，CBA猕猴的处置指数显着降低，表明在包括骨骼肌在内的目标时机处的胰岛素反应受损。科学文献中的报告和我们的初步数据支持了以下核心假设：CBA在SIV感染的猕猴的骨骼肌中下降了胰岛素介导的合成代谢反应。作为申请人培训计划的一部分进行的拟议研究将使用一种集成的方法来评估以下特定目的：1）测试CBA在SIV感染的麦克拉麦克斯的骨骼肌肉中胰岛素介导的葡萄糖摄取和糖原合成的预测，以确定胰岛素的插座（s）插入胰岛素的插M麦克斯（S），以确定胰岛素的插图（S）。在CBA管理之后。拟议研究的发现将提供证据，以阐明CBA和SIV/ART结合后胰岛素信号传导骨骼肌的潜在分子演变，并可能会深入了解旨在改善患有HIV/AIDS患者的代谢失调的治疗靶标。