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.

抽象的 此Ruth L. Kirschstein NRSA F30应用的主要目的是提供基础。 为申请人准备学术医疗职业。申请人的大部分职业发展都将到来 从高优先级的艾滋病毒/艾滋病合并症相关的研究中，她将有无价的机会 使用公认的慢性酒精临床前模型（CBA）和 猿猴免疫缺陷病毒（SIV）感染。在艾滋病毒感染者中，处于风险的酒精饮酒的可能性是 （PLWH）与普通人群一样。抗逆转录病毒疗法（ART）的PLWH具有接近正常的寿命 期待，但代谢合并症的患病率有所提高，需要研究 在HIV背景下研究代谢失调的病理生理机制。我们小组的研究 已经表明，在PLWH和 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 摄取，临床前研究表明酒精会降低SKM胰岛素敏感性。初步数据 该应用程序生成 进一步表明酒精会导致SKM功能障碍。我们小组的先前工作证明了 肌管中的CBA介导的变化反映了SKM中看到的内容，我们将利用培养的肌管反映 在我们提出的实验中，SKM中看到的变化。细胞外蔬菜（EV）介导细胞变化 通过运输包括microRNA（miRNA）在内的病理和治疗状况 细胞。 miRNA是调节基因表达的小型非编码RNA，并由 CBA和胰岛素抵抗。初步和以前的数据表明，CBA导致较低的表达 Skm特异性miRNA-206在血浆EV和SIV感染猕猴的SKM中，以及miRNA-206涉及 在SKM胰岛素依赖性葡萄糖摄取中。综上所述，我们的初步数据和出版的文献支持 假设是酒精介导的肌管外囊泡miRNA货物的改变有助于 为了恶化SIV感染中的肌管胰岛素敏感性。拟议的研究将采用各种各样的 使用两个特定目的测试假设的最新技术：（1）CBA-ADMINISSIRTION改变Myotube- SIV感染的猕猴中的EV型材，以及（2）Myotube衍生的EV miRNA货物CBA管理的货物 SIV感染的猕猴会降低肌管胰岛素敏感性。拟议研究的发现将提供 洞悉电动汽车在酒精介导的SKM胰岛素不敏感性中的作用在SIV感染中。另外，提议 项目旨在说明电动汽车在改善酒精介导的SKM功能障碍方面的治疗潜力。和 一个强大的心理团队致力于发展全面的身体科学家，完成了拟议的 高优先级艾滋病毒/艾滋病合并症相关研究的培训计划将确保申请人准备好 从事学术医学职业。