DMB (3,3-dimethyl-1-butanol) as a novel translational strategy for preventing and treating gut dysbiosis-associated arterial aging

DMB（3,3-二甲基-1-丁醇）作为预防和治疗肠道菌群失调相关动脉老化的新型转化策略

• 批准号: 9977931
• 负责人: DOUGLAS R SEALS
• 金额: $ 19.78万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977931
• 关键词: 1-Butanol; Address; Advanced Glycosylation End Products; Adverse effects; Age; Aging; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Availability; Blood Circulation; C57BL/6 Mouse; Caliber; Cardiovascular Diseases; Cause of Death; Choline; Clinical; Collagen; Data; Development; Diet; Disease; Elastin; Elderly; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Food; Functional disorder; Future; Genome; Goals; Health; Human; Impairment; Inflammation; Inflammatory; Ingestion; Laboratories; Lead; Levocarnitine; Link; Liver; Longevity; Lyase; Mechanics; Mediating; Mediator of activation protein; Modeling; Mus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Oxidative Stress; Oxides; Pathway interactions; Patients; Physiologic pulse; Physiological; Physiology; Phytochemical; Pre-Clinical Model; Prevention; Preventive; Process; Production; Public Health; Reactive Oxygen Species; Research; Risk; Rodent Model; Signal Transduction; Structural Protein; Structure; Superoxide Dismutase; Superoxides; Therapeutic; Translations; Vascular Endothelium; Vascular remodeling; Water; Work; age related; arterial stiffness; cardiovascular disorder risk; cardiovascular risk factor; clinical development; drinking water; dysbiosis; endothelial dysfunction; experimental study; functional decline; gut bacteria; gut colonization; gut microbes; gut microbiome; healthspan; human model; improved; inhibitor/antagonist; insight; intimal medial thickening; microbial; microbial community; microbiome; middle age; mimetics; mouse model; novel; novel therapeutic intervention; novel therapeutics; preservation; prevent; response; translation to humans; translational approach; trimethylamine; trimethyloxamine; vascular endothelial dysfunction; vascular inflammation; vasoconstriction

PROJECT SUMMARY/ABSTRACT Age-related arterial dysfunction is the primary risk factor for cardiovascular diseases (CVD). One possible link between aging and arterial dysfunction is the gut microbiome, a strong modulator of host physiology that is influenced by age and that may provide novel mechanistic targets for preventing or reversing arterial dysfunction. Ongoing studies in our laboratory are the first to indicate that age-related adverse changes in the gut microbiome, termed gut dysbiosis, influence the development of arterial dysfunction. One consequence of gut dysbiosis is increased production of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO), which has been linked to the development of atherosclerosis in both rodent models and humans. Our preliminary data show that TMAO also independently induces arterial dysfunction, suggesting TMAO contributes to declines in arterial function that precede the development of clinical CVD. Further, our pilot data suggest that inhibition of TMAO with the recently identified compound 3,3-dimethyl-1- butanol (DMB) may reverse arterial dysfunction in old mice, suggesting that DMB may hold clinical promise for reducing the age-associated increase in risk of CVD. Indeed, DMB is a naturally-occurring phytochemical with no known adverse effects, making it an excellent candidate for translation to humans. The purpose of this R21 application is to investigate the efficacy of DMB for (1) preventing the development of arterial dysfunction in mice when initiated in midlife (i.e., before the onset of dysfunction), and (2) reversing or, at the least, improving already established arterial dysfunction in old mice. In addition, we will use several state-of-the-art mechanistic probes to gain insight into the mechanisms underlying the proposed beneficial effects of DMB (Aim 3). In particular, we will investigate whether DMB preserves/improves arterial function via suppression of superoxide-driven oxidative stress, the predominant mechanistic process that mediates age- related arterial dysfunction. Overall, the proposed research has the potential to identify a novel therapeutic strategy to prevent and treat age-related arterial dysfunction, thereby reducing risk of CVD, and represents a critical step in the translation of DMB to humans for preventing CVD and other age-related diseases and disorders. Use of a mouse model of human aging affords a unique opportunity to assess the long-term preventive effects of DMB. Furthermore, this research will address 2 recently announced strategic directions of NIA: 1) to understand interactions between the microbiome and aging and its contributions to declining health and function, and 2) to identify compounds that hold the promise of increasing healthy lifespan. Finally, the proposed studies will establish a new experimental translational paradigm (model) for manipulating gut microbial pathways to determine their effects on CV and physiological functions that influence human healthspan.

项目摘要/摘要 年龄相关性动脉功能障碍是心血管疾病(CVD)的主要危险因素。一种可能 衰老和动脉功能障碍之间的联系是肠道微生物组，它是宿主生理的强大调节器， 受年龄的影响，这可能为预防或逆转动脉提供新的机制靶点 功能障碍。我们实验室正在进行的研究首次表明，与年龄相关的不良变化 肠道微生物群，被称为肠道生物失调，影响动脉功能障碍的发展。 肠道菌群失调的一个后果是有害的肠源性代谢物的产生增加。 三甲胺N-氧化物(TMAO)与两种啮齿动物动脉粥样硬化的发展有关 模特和人类。我们的初步数据显示，TMAO还独立地导致动脉功能障碍， 提示TMAO是临床CVD发生前动脉功能下降的原因之一。 此外，我们的试验数据表明，最近发现的化合物3，3-二甲基-1-甲氧基-3，3-二甲基-1-甲氧基苯并三甲氧基甲苯(TMAO)的抑制作用。 丁醇(DMB)可逆转老年小鼠动脉功能障碍，提示DMB可能具有治疗老年小鼠动脉功能障碍的临床前景 降低与年龄相关的心血管疾病风险增加。事实上，DMB是一种自然产生的植物化学物质， 没有已知的副作用，使其成为翻译成人类的绝佳候选。 此R21应用程序的目的是研究DMB对于(1)防止发育的有效性 在中年开始时(即在功能障碍开始之前)小鼠的动脉功能障碍，以及(2)逆转 或者，至少改善老年小鼠已经确立的动脉功能障碍。此外，我们还将使用几个 最先进的机械探索，深入了解拟议的益处背后的机制 DMB的影响(目标3)。特别是，我们将研究DMB是否通过以下途径保护/改善动脉功能 抑制超氧化物驱动的氧化应激，这是调节衰老的主要机制过程- 相关的动脉功能障碍。 总体而言，拟议的研究有可能确定一种新的预防和治疗策略 与年龄相关的动脉功能障碍，从而降低心血管疾病的风险，是 将DMB翻译给人类用于预防心血管疾病和其他与年龄相关的疾病和障碍。使用 人类衰老的小鼠模型为评估DMB的长期预防效果提供了一个独特的机会。 此外，这项研究将涉及NIA最近宣布的两个战略方向：1)理解 微生物组与衰老之间的相互作用及其对健康和功能下降的贡献，以及2) 确定那些有望延长健康寿命的化合物。最后，拟议的研究将 建立一种新的实验性翻译范式(模型)来操纵肠道微生物途径 确定它们对影响人类健康的CV和生理功能的影响。