Alcohol-mediated Clock genes interfere with lung injury and repair

酒精介导的时钟基因干扰肺损伤和修复

• 批准号: 10587621
• 负责人: VIRANUJ SUEBLINVONG
• 金额: $ 52.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587621
• 关键词: ARNT gene; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Alcohol abuse; Alcohols; Animal Model; Antisense Oligonucleotides; Attenuated; Bleomycin; Brain; Cells; Chest imaging; Chronic; Cicatrix; Circadian Dysregulation; Collagen; Complement; Custom; Data; Deposition; Diagnosis; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gel; Genes; Goals; Immunoprecipitation; In Vitro; Incidence; Inflammatory; Injury; Intestines; Knockout Mice; Lentivirus Vector; Liver; Lung; Lung diseases; Measures; Mediating; Molecular; Mus; Muscle; Myofibroblast; Nuclear; Organ; Orphan; Pathogenesis; Pathway interactions; Physiological; Plasmids; Preclinical Testing; Predisposition; Public Health; RNA; Recovery; Research; Retinoids; Risk; Role; Signal Pathway; Stress; Structure of parenchyma of lung; Supportive care; Survivors; TGFB1 gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; United States; Untranslated RNA; attenuation; chromatin immunoprecipitation; chronic alcohol ingestion; circadian; design; experience; experimental study; health related quality of life; improved outcome; in vivo; inhibitor; lung injury; lung repair; mortality; novel; overexpression; posttranscriptional; pre-clinical; preventive intervention; problem drinker; receptor; repaired; response; therapeutically effective; tissue injury; tissue repair; transcription factor; transcriptomics; wound healing

In the United States, the acute respiratory distress syndrome (ARDS) remains a significant public health problem. Despite substantial efforts to improve the outcome, ~ 80% of ARDS survivors experience reduced health-related quality of life and have fibrotic changes on chest imaging for up to 5 years after diagnosis. Chronic alcohol abuse significantly increases the incidence of, and mortality from, ARDS, without directly causing lung damage. Emerging data show that alcohol interferes with the circadian signaling pathway in the liver and intestine which, in turn, render tissue susceptibility to injury and fibrosis. The circadian pathway consists of multiple transcription factors which mediate various organ physiological functions through its regulatory networks. It is known that some of circadian pathway molecules can regulate non-coding RNAs and vice versa, non-coding RNAs can regulate circadian pathway molecules. In this proposal, we present preliminary data showing that alcohol promotes circadian pathway dysfunction in the lung through alterations of circadian pathway molecules BMAL1 and nuclear factor Retinoid-Related Orphan Receptor-alpha (RORα). We believe these changes lead to alcohol-induced TGFβ1 by suppressing RORα-miR-139 activity. Further, we identified the circ-RORα-miR-155 axis as a novel regulatory mechanism of BMAL1. These results led us to hypothesize that chronic alcohol ingestion disrupts circadian pathway signaling and the circ-RORα-miR-155 axis which, thereby perturbing the RORα-miR-139 axis which, in turn, render lung susceptibility toward fibroproliferative disrepair following acute injury. The experimental approaches are designed to test this hypothesis. These studies will provide a firm scientific basis for the underlying mechanisms by which alcohol interferes with tissue repair following lung injury.

在美国，急性呼吸窘迫综合征（ARDS）仍然是一个重要的公共卫生问题 问题.尽管为改善预后做出了大量努力，但约80%的ARDS幸存者的呼吸道阻力降低， 与健康相关的生活质量，并在诊断后长达5年的胸部影像学检查中出现纤维化变化。 慢性酒精滥用显著增加了ARDS的发病率和死亡率，但与此无关。 导致肺部损伤。新出现的数据表明，酒精干扰昼夜信号通路， 这又使组织对损伤和纤维化敏感。昼夜节律通路 由多个转录因子组成，这些转录因子通过其 监管网络。已知一些昼夜节律通路分子可以调节非编码RNA， 反之亦然，非编码RNA可以调节昼夜节律通路分子。在这份提案中，我们提出 初步数据显示，酒精通过改变肺内的 昼夜节律通路分子BMAL 1和核因子类维生素A相关孤儿受体-α（RORα）。我们 认为这些变化通过抑制RORα-miR-139活性导致酒精诱导的TGFβ1。我们还 将circ-RORα-miR-155轴确定为BMAL 1的新调控机制。这些结果使我们 假设慢性酒精摄入破坏昼夜节律通路信号传导和circ-RORα-miR-155 轴，从而干扰RORα-miR-139轴，进而使肺对 急性损伤后纤维增生性破损。实验方法旨在验证这一点 假说.这些研究将为酒精的潜在机制提供坚实的科学基础。 干扰肺损伤后的组织修复。