Alcohol-induced Skeletal Muscle Insulin Insensitivity in SIV/HIV: Myotube-derived Extracellular Vesicle-mediated Mechanisms

SIV/HIV 中酒精诱导的骨骼肌胰岛素不敏感：肌管衍生的细胞外囊泡介导的机制

• 批准号: 10670379
• 负责人: Brianna Leilani Bourgeois
• 金额: $ 4.2万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670379
• 关键词: Adhalin; Affect; Alcohol consumption; Alcoholic Hepatitis; Alcohols; Binding; Cells; Chronic; Data; Diabetes Mellitus; Electroporation; Endocrine; Endocrinology; Ensure; Fellowship; Fostering; Functional disorder; Funding; Future; GLUT 4 protein; Gene Expression; General Population; Glucose; HIV; HIV/AIDS; Health Sciences; Hepatocyte; Impairment; In Vitro; Insulin; Insulin Resistance; Insulin Signaling Pathway; Laboratories; Life Expectancy; Lipid Bilayers; Lipids; Literature; Liver diseases; Louisiana; Macaca; Macaca mulatta; Measures; Mediating; Medical; Medical Research; Medicine; Mentors; Metabolic; MicroRNAs; Modeling; Mus; Muscle; Muscle Fibers; Myoblasts; National Institute on Alcohol Abuse and Alcoholism; National Research Service Awards; Pathologic; Pathway interactions; Persons; Phosphorylation; Physicians; Physiological; Plasma; Pre-Clinical Model; Prevalence; Proteins; Publishing; RNA; Regulation; Research; Role; SIV; Scientist; Signal Transduction; Site; Skeletal Muscle; Skeletal Myoblasts; Structure of beta Cell of islet; Techniques; Testing; Therapeutic; Training; Universities; Untranslated RNA; Virus Diseases; Western Blotting; Work; alcohol research; alcohol risk; antiretroviral therapy; career; career development; comorbidity; differential expression; experimental study; extracellular vesicles; glucose uptake; improved; in vivo; insight; insulin sensitivity; insulin signaling; intercellular communication; interest; miRNA expression profiling; monocyte; nanoparticle; nerve stem cell; novel; paracrine; pre-clinical research; preclinical study; research study; skeletal muscle differentiation; skeletal muscle metabolism; training opportunity; translational potential; translational study; translational therapeutics; vesicular release

Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the groundwork that will prepare the applicant for an academic medical career. Much of the applicant’s career development will come from work in High Priority HIV/AIDS comorbidity-related research, and she will have the invaluable opportunity to carry out high quality research using a well-established preclinical model of chronic binge alcohol (CBA) and simian immunodeficiency virus (SIV) infection. At-risk alcohol use is twice as likely in people living with HIV (PLWH) as it is in the general population. PLWH on antiretroviral therapy (ART) have a near normal life expectancy, but there is an increase in prevalence of metabolic comorbidities, requiring a need for research studying pathophysiological mechanisms of metabolic dysregulation in the context of HIV. Studies from our group have shown that at-risk alcohol use and CBA is associated with impaired insulin/glucose dynamics in PLWH and in SIV-infected macaques, respectively. Skeletal muscle (SKM) is a major site of insulin-dependent glucose uptake, and preclinical studies indicate that alcohol decreases SKM insulin sensitivity. Preliminary data generated for this application suggest that CBA dysregulates proteins in the insulin signaling pathway in SKM, further indicating that alcohol leads to SKM dysfunction. With previous work from our group demonstrating that CBA-mediated alterations in myotubes reflect what is seen in SKM, we will utilize cultured myotubes to reflect changes seen in SKM in our proposed experiments. Extracellular vesicles (EVs) mediate cellular changes in pathologic and therapeutic conditions by transporting bioactive cargo, including microRNAs (miRNAs), between cells. miRNAs are small non-coding RNAs that regulate gene expression and are differentially expressed by CBA and insulin resistance. Preliminary and previous data suggests that CBA leads to lower expression of the SKM specific miRNA-206 in plasma EVs and the SKM of SIV-infected macaques, and miRNA-206 is implicated in SKM insulin-dependent glucose uptake. Taken together, our preliminary data and published literature support the hypothesis, that alcohol-mediated alterations in myotube extracellular vesicle miRNA cargo contribute to decreased myotube insulin sensitivity in SIV infection. The proposed study will employ a wide variety of state-of- the-art techniques to test the hypothesis using two specific aims: (1) CBA-administration alters myotube- derived EV profile in SIV-infected macaques, and (2) myotube-derived EV miRNA cargo of CBA-administered SIV-infected macaques decreases myotube insulin sensitivity. Findings from the proposed studies will provide insight on the role of EVs in alcohol-mediated SKM insulin insensitivity in SIV infection. Additionally, the proposed project aims to illustrate the therapeutic potential of EVs in improving alcohol-mediated SKM dysfunction. With a strong mentoring team committed to developing a well-rounded physician scientist, completion of the proposed training plan in High Priority HIV/AIDS comorbidity-related research will ensure that the applicant is ready to embark on a career in academic medicine.

摘要 这个Ruth L的主要目的。Kirschstein NRSA F30应用程序是为了提供基础， 为申请人的学术医学生涯做好准备。申请人的大部分职业发展将来自 从工作中的高优先级艾滋病毒/艾滋病共病相关的研究，她将有宝贵的机会 使用完善的慢性酗酒（CBA）临床前模型进行高质量的研究， 猴免疫缺陷病毒（SIV）感染。艾滋病毒感染者中有风险的酒精使用是艾滋病毒感染者的两倍 （PLWH），因为它是在一般人群中。接受抗逆转录病毒治疗的艾滋病毒携带者生活接近正常 预期，但代谢合并症的患病率增加，需要进行研究 研究HIV背景下代谢失调的病理生理机制。我们小组的研究 研究表明，高危饮酒和CBA与PLWH中胰岛素/葡萄糖动力学受损相关， 在SIV感染的猕猴中。骨骼肌（SKM）是胰岛素依赖性葡萄糖的主要部位 临床前研究表明，酒精会降低SKM胰岛素敏感性。初步数据 为该应用产生的结果表明CBA在SKM中的胰岛素信号传导途径中失调蛋白， 进一步表明酒精导致SKM功能障碍。我们小组之前的工作表明， CBA介导的肌管改变反映了SKM中所见，我们将利用培养的肌管来反映 在我们提出的实验中看到的SKM变化。细胞外囊泡（EV）介导细胞的变化， 病理和治疗条件之间的运输生物活性货物，包括微RNA（miRNA）， 细胞miRNAs是一种小的非编码RNA，调节基因表达，并通过 CBA与胰岛素抵抗初步和以前的数据表明，CBA导致低表达的 血浆EV和SIV感染的猕猴的SKM中的SKM特异性miRNA-206，并且miRNA-206涉及 胰岛素依赖性葡萄糖摄取。综上所述，我们的初步数据和已发表的文献支持 这一假说认为，酒精介导的肌管细胞外囊泡miRNA货物的改变有助于 SIV感染时肌管胰岛素敏感性降低。拟议的研究将采用各种各样的 最先进的技术来测试假设使用两个特定的目的：（1）CBA管理改变肌管， 在SIV感染的猕猴中衍生的EV概况，和（2）CBA施用的肌管衍生的EV miRNA货物 SIV感染的猕猴降低肌管胰岛素敏感性。拟议研究的结果将提供 深入了解EV在SIV感染中酒精介导的SKM胰岛素不敏感性中的作用。此外，拟议的 该项目旨在说明EV在改善酒精介导的SKM功能障碍方面的治疗潜力。与 一个强大的指导团队，致力于发展一个全面的医生科学家，完成拟议的 高优先级艾滋病毒/艾滋病共病相关研究的培训计划将确保申请人准备好 开始从事学术医学