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: 9310227
• 负责人: Liz Simon
• 金额: $ 16.89万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310227
• 关键词: AIDS/HIV problem; Address; Adult; Affect; Alcohols; Anti-Infective Agents; Anti-Retroviral Agents; Area; Back; Basic Science; Biometry; Blood Circulation; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Chronic; Comorbidity; Complement; Data; Environment; Epigenetic Process; Functional disorder; Future; GDF8 gene; Gene Expression; Gene Targeting; 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; Pharmaceutical Preparations; 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; Stem cells; 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; 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; prevent; regenerative; repaired; satellite cell; skeletal muscle wasting; skills; stem cell biology; 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.

项目概要/摘要 NIH 指导研究科学家发展奖 (K01) 申请的目的是提供 在三个关键领域进行额外的培训和研究技能，以便在以下领域进行高度优先的研究： 具体来说，候选人将能够熟练地处理与艾滋病毒/艾滋病相关的合并症。 转化研究重点关注酒精介导的代谢并发症 接受抗逆转录病毒治疗的早年感染艾滋病毒的申请人是一个有前途的人。 拥有干细胞和信号传导研究记录的科学家，她现在建议将其整合 与酒精诱导的表观遗传改变领域一起制定综合全面的计划。 研究技能将培养候选人在表观遗传分析、生物统计学和转化方面的专业知识 研究计划将重点阐明酒精引起的损伤的机制。 从慢性酗酒 (CBA) 中分离出的 SIV/HIV 成肌细胞的骨骼肌 (SKM) 再生。 施用后的猕猴显示出肌源性基因表达降低和分化成 在体外培养时观察到肌管分化受损。 体外酒精暴露，表明这些成肌细胞具有保留基因表达的“记忆” 初步证据表明肌肉特异性 microRNA (myomiR) 也出现失调。 CBA 管理的感染 SIV 的猕猴的 SKM 导致了 CBA 损害 SKM 的假设 通过肌源性基因转录的表观遗传修饰实现 SIV/HIV 感染的再生。 该假设将通过三个具体目标进行严格检验。第一个目标将检验 CBA 的预测。 导致成肌细胞 myomiR 表达和分化潜力下降。 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。 受过原位杂交技术培训，用于确定成肌细胞培养物中 myomiR 的表达。 第二个目标将测试 CBA 诱导的成肌细胞组蛋白修饰有助于的预测 使用分子技术，myomiRs 的靶基因将会降低。 第三个目标是确定组蛋白脱乙酰酶 (HDAC) 活性和组蛋白修饰。 将确定一组人群循环中 myomiR 表达改变的临床相关性 患有艾滋病毒/艾滋病 (P L W H A) 并患有酒精使用障碍 (AUD) 的 myomiR 循环水平将降低。 与 AUD 和肌肉力量（握力计）相关，以确定其潜在用途 拟议和未来研究的总体目标是确定肌源性功能受损的指标。 目标是通过物理（运动）或药物干预来改善骨骼肌功能。 综合转化和跨学科培训计划将支持候选人晋升为 在酒精诱导的骨骼肌表观遗传调节领域的独立生产事业 再生潜力，并将有助于对进行高水平研究所需的劳动力进行研究培训 优先针对非人类灵长类动物和艾滋病病毒感染者进行艾滋病毒/艾滋病相关研究。