Alcohol-induced myomiR dysregulation: mechanisms of impaired skeletal muscle regeneration in SIV/HIV

酒精引起的 myomiR 失调：SIV/HIV 骨骼肌再生受损的机制

• 批准号: 9976400
• 负责人: Liz Simon
• 金额: $ 16.63万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976400
• 关键词: AIDS/HIV problem; Address; Adult; Affect; Alcohols; Anti-Infective Agents; Area; Back; Basic Science; Biometry; Blood Circulation; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Chronic; Complement; Data; Environment; Epigenetic Process; Functional disorder; Future; GDF8 gene; Gene Expression; Genes; Genetic Transcription; Goals; Growth and Development function; HDAC4 gene; HIV; HIV Infections; Hand; Hand Strength; Histone Deacetylase; Impairment; In Situ Hybridization; In Vitro; Incidence; Individual; Inflammatory; Intervention; Laboratories; Macaca; Macaca mulatta; Mediating; Memory; Mentored Research Scientist Development Award; Mentors; Metabolic; MicroRNAs; Mission; Modification; Molecular; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Myoblasts; Natural regeneration; Pathway interactions; Patients; Persons; Pharmacology; Physical Exercise; Plasma; Play; Population; Proteins; Quality of life; Recording of previous events; Regulation; Research; Research Infrastructure; Research Priority; Research Proposals; Research Training; Role; SIV; Scientist; Signal Transduction; Skeletal Muscle; Techniques; Testing; Time; Training; Transfection; Translational Research; Ubiquitin; United States; United States National Institutes of Health; Untranslated RNA; Virus Diseases; aged; alcohol exposure; alcohol use disorder; antiretroviral therapy; career; chronic alcohol ingestion; clinically relevant; cohort; comorbidity; drug of abuse; grasp; histone modification; improved; in vivo; lean body mass; lifestyle intervention; male; mortality; multicatalytic endopeptidase complex; muscle form; muscle regeneration; muscle strength; myocyte-specific enhancer-binding-factor 2C; myogenesis; nonhuman primate; premature; preservation; prevent; regenerative; repaired; satellite cell; skeletal muscle wasting; skills; stem cell biology; stem cells; targeted treatment; transcription factor

Project Summary/Abstract The objective of this NIH Mentored Research Scientist Development Award (K01) application is to provide additional training and research skill sets in three critical areas needed to conduct high priority research in HIV/AIDs-associated comorbidities. Specifically, the candidate will be skilled to conduct basic and translational research focused on the alcohol-mediated metabolic complications prevalent in the prematurely aged individuals infected with HIV on antiretroviral therapy. The applicant is a promising scientist with a track record of research in stem cells and signaling, which she now proposes to integrate with the field of alcohol-induced epigenetic alterations. The integrated and comprehensive plan to develop research skills will build the candidate’s expertise in epigenetic analysis, biostatistics, and translational research. The research proposal will focus on elucidating the mechanisms of alcohol-induced impairment of skeletal muscle (SKM) regeneration in SIV/HIV. Myoblasts isolated from chronic binge alcohol (CBA)- administered macaques show decreased myogenic gene expression and potential to differentiate into myotubes when cultured in vitro. Impaired myogenic differentiation was observed in the absence of in vitro alcohol exposure, suggesting that these myoblasts had a “memory” that preserved gene expression changes. Preliminary evidence also suggests dysregulated muscle-specific microRNAs (myomiRs) in the SKM of CBA-administered SIV-infected macaques leading to the hypothesis that CBA impairs SKM regeneration in SIV/HIV infection through epigenetic modifications of myogenic gene transcription. This hypothesis will be critically tested by three specific aims. The first aim will test the prediction that CBA results in decreased myoblast myomiR expression and differentiation potential. To address this, the candidate will use her existing skills in stem cell culture and molecular techniques. In addition, she will be trained in in situ hybridization techniques for determining expression of myomiRs in myoblast cultures. The second aim will test the prediction that CBA-induced myoblast histone modifications contributes to decreased myogenic differentiation potential. Using molecular techniques target genes of myomiRs will be validated, histone deacetylase (HDAC) activity, and histone modifications will be determined. The third aim will establish the clinical relevance of altered myomiR expression in the circulation in a cohort of persons living with HIV/AIDS ( P L W H A ) with alcohol use disorders (AUD). Circulating levels of myomiRs will be correlated with AUD and muscle strength (hand grip dynamometer) to establish their potential use as indicators of impaired myogenic function. The overarching goal of the proposed and future studies is to identify targets to improve skeletal muscle function using physical (exercise) or pharmacological interventions. The integrated translational and transdisciplinary training plan will support the candidate’s progression to an independent productive career in the field of alcohol- induced epigenetic modulation of skeletal muscle regenerative potential and will contribute to the research training of the workforce required to conduct high priority HIV/AIDS related research in non-human primates and PLWHA.

项目摘要/摘要 NIH指导研究科学家发展奖（K01）的应用程序的目的是提供 在进行高度优先研究所需的三个关键领域的其他培训和研究技能集 艾滋病毒/艾滋病相关的合并症。具体而言，候选人将熟练进行基本和 转化研究的重点是酒精介导的代谢并发症 过早老年人感染了抗逆转录病毒治疗的HIV。申请人是承诺 科学家在干细胞和信号传导方面具有研究记录，她现在提出整合 随着酒精诱导的表观遗传改变的领域。制定的综合综合计划 研究技能将建立候选人在表观遗传分析，生物统计学和翻译方面的专业知识 研究。研究建议将重点阐明酒精诱导的损害的机制 SIV/HIV中的骨骼肌（SKM）再生。从慢性暴饮（CBA）中分离出的成肌细胞 - 给药猕猴显示肌源基因表达降低，并且有潜力分化为 体外培养时肌管。在没有In的情况下观察到肌原分化受损 体外酒精暴露，表明这些成肌细胞具有保存基因表达的“记忆” 更改。初步证据还表明，在 CBA管理的SKM，由SIV感染的猕猴导致CBA损害SKM的假设 通过肌原基因转录的表观遗传学修饰，SIV/HIV感染的再生。这 假设将通过三个特定目标进行严格检验。第一个目标将测试CBA的预测 导致肌细胞肌瘤表达和分化潜力降低。为了解决这个问题， 候选人将利用她在干细胞培养和分子技术方面的现有技能。此外，她会 经过培训的原位杂交技术，用于确定肌细胞培养物中肌瘤的表达。这 第二个目标将测试CBA引起的肌细胞Hisstone修改的预测有助于 肌源分化潜力降低。使用分子技术靶向肌瘤的基因将是 经过验证的组蛋白脱乙酰基酶（HDAC）活性，将确定组蛋白修饰。第三个目标 将建立在人群中循环中肌瘤表达改变的临床相关性 患有艾滋病毒/艾滋病（P L W H A）患有酒精使用障碍（AUD）。循环水平的肌瘤水平将是 与AUD和肌肉强度（手持握力计）相关，以确定其潜在用途 肌原性功能受损的指标。拟议的和未来的研究的总体目标是确定 使用物理（运动）或药物干预措施改善骨骼肌功能的目标。这 综合翻译和跨学科培训计划将支持候选人的发展 酒精引起的骨骼肌表观遗传调节领域的独立生产事业 再生潜力，并将有助于研究高级劳动力的研究培训 非人类隐私和PLWHA的优先艾滋病毒/艾滋病相关研究。