Alcohol & Metabolic Comorbidities in PLWHA; Evidence-Driven Interventions

酒精

• 批准号: 10020294
• 负责人: PATRICIA E. MOLINA
• 金额: $ 35.36万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020294
• 关键词: AIDS/HIV problem; ARHGEF5 gene; Adrenergic Agonists; Adult; Aerobic Exercise; Aging; Alcohol consumption; Alcohols; Behavior; Caring; Chronic; Chronic Disease; Cross-Sectional Studies; Data Analyses; Ensure; Environment; Exercise; Fasting; Gene Expression; Glucose; HIV; HIV Infections; Health; Health Sciences; Healthcare; Homeostasis; Human; Impairment; In Vitro; Individual; Inflammatory; Insulin; Insulin Resistance; Intervention; Louisiana; Macaca; Macaca mulatta; Metabolic; Mitochondria; Modeling; Myopathy; Oxygen Consumption; Pathway interactions; Patients; Pattern; Persons; Phase; Phenotype; Physical activity; Prediabetes syndrome; Preventive measure; Prospective Studies; Publishing; Quality of life; Research Personnel; Resources; Risk; Risk Factors; SIV; Skeletal Muscle; Social Environment; Substance abuse problem; Testing; Translating; United States; Universities; alcohol research; antiretroviral therapy; base; blood glucose regulation; chronic alcohol ingestion; cohort; comorbidity; cost; efficacy testing; euglycemia; exercise intervention; glycemic control; immunosenescence; improved; indexing; male; mortality; muscle form; nonhuman primate; novel; oral glucose tolerance; pre-clinical; recruit; regenerative; response; skeletal muscle wasting; synergism; translational approach; translational study

Abstract Chronic alcohol consumption is the most common and costly form of substance abuse in the United States and is highly prevalent in persons living with HIV/AIDS (PLWHA). Antiretroviral therapy (ART) has greatly reduced HIV/AIDS mortality, and HIV infection is emerging as a chronic disease with enhanced risk for metabolic comorbidities like insulin resistance and prediabetes. Chronic hazardous alcohol drinking (AUDIT score ≥5) is also a risk factor for these comorbidities. Our studies in chronic binge alcohol (CBA) administered simian immunodeficiency virus (SIV)-infected (CBA/SIV) male rhesus macaques (ART-treated and -naïve) have shown that dysfunctional skeletal muscle (SKM) is associated with impaired glucose regulation despite normal fasting glycemia. This UH2UH3 application proposes to leverage our ongoing translational study, (P60 AA009803; PI: Molina) Aging in Louisiana: Immunosenescence, hiV, & socioEnvironmental factors (ALIVE) Study in a cohort of in-care adult PLWHA to translate our findings from the macaque model. We propose a combined two phase cross-sectional and prospective study to test the prediction that a higher proportion of PLWHA with AUDIT ≥5 with subclinical fasting dysglycemia will present with impaired oral glucose tolerance. We hypothesize that dysfunctional metabolic SKM and loss of mitochondrial homeostatic mechanisms are important mechanisms underlying this metabolic comorbidity. Studies proposed in the UH2 phase aim to validate this “preintervention” hypothesis. Studies proposed in the UH3 phase will test the hypothesis that SKM metabolic function and mitochondrial homeostasis can be enhanced (or restored) by aerobic exercise, improving glycemic control. The hypotheses to be tested are based on evidence derived from our comprehensive characterization of metabolic dysregulation in CBA/SIV macaques and on preliminary findings obtained from interim analysis of data collected from PLWHA recruited to our ALIVE study. Our bi-directional translational approach ensures relevance of our findings from non-human primates to the human condition. The proposed study will be conducted by an interdisciplinary team of investigators with established expertise on studies of the impact of alcohol on metabolic comorbidities in the SIV/HIV infected host. This project will benefit from the rich scientific environment, and outstanding Experimental and Analytical Resource Cores of the LSUHSC Comprehensive Alcohol Research Center. The expected results should have a profound impact on ameliorating the risk of developing metabolic comorbidities that impose a significant burden on the health care of PLWHA. These study results will serve to inform larger scale interventions promoting a more rigorous approach to identification of at-risk PLWHA that may benefit from preventive measures to increase physical activity and modify behavior leading to improved health, quality of life, and possibly decreased hazardous alcohol drinking.

抽象的 长期饮酒是美国最常见和昂贵的滥用药物的形式， 在患有艾滋病毒/艾滋病（PLWHA）的人中非常普遍。抗逆转录病毒疗法（ART）大大减少了 艾滋病毒/艾滋病死亡率和艾滋病毒感染正在成为一种慢性疾病，其代谢风险增加 合并症，例如胰岛素抵抗和糖尿病前期。慢性危害酒精饮酒（审计得分≥5）为 这也是这些合并症的危险因素。我们在慢性酒精（CBA）的研究 免疫缺陷病毒（SIV）感染（CBA/SIV）雄性猕猴（Art-Treateat and-Neïve）具有 表明功能失调的骨骼肌（SKM）与葡萄糖调节受损有关 禁食糖。该UH2UH3申请提案要利用我们正在进行的翻译研究（P60） AA009803; PI：Molina）在路易斯安那州的衰老：免疫衰老，艾滋病毒和社会环境因素（活着） 在一系列护理成人PLWHA中进行研究，以从猕猴模型中转化我们的发现。我们提出了一个 结合了两个相横截面和前瞻性研究，以测试以下预测。 带有亚临床空腹血糖的审计≥5的PLWHA会出现口服葡萄糖耐受性受损。 我们假设功能失调的代谢SKM和线粒体稳态机制的丧失是 这种代谢合并症的重要机制。 UH2阶段提出的研究旨在 验证此“干预前”假设。在UH3阶段提出的研究将检验SKM的假设 可以通过有氧运动来增强（或恢复），代谢功能和线粒体稳态， 改善血糖控制。要测试的假设是基于从我们的 CBA/SIV猕猴和初步发现中代谢失调的全面表征 从从PLWHA收集到的数据中收集到我们活着的研究的临时分析。我们的双向 翻译方法可确保我们发现从非人类素数到人类状况的相关性。 拟议的研究将由具有既定专业知识的调查员跨学科团队进行 关于酒精对SIV/HIV感染宿主代谢合并症的影响的研究。这个项目将 受益于丰富的科学环境，以及出色的实验和分析资源核心 LSUHSC综合酒精研究中心。预期的结果应该产生深远的影响 改善发展代谢合并症的风险，这对健康造成了重大燃烧 照顾PLWHA。这些研究结果将有助于大规模干预措施，以促进更严格的 识别高风险PLWHA的方法，该方法可能会受益于预防测量以增加物理 活动并修改行为，导致健康，生活质量改善，并可能降低危险 饮酒。