Regulatory Role of MicroRNAs in Aging-related Abdominal Aortic Aneurysm Disease

MicroRNA 在衰老相关腹主动脉瘤疾病中的调节作用

• 批准号: 9897408
• 负责人: Philip S Tsao
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897408
• 关键词: 3' Untranslated Regions; Abdominal Aortic Aneurysm; Acceleration; Age; Age-Years; Aging; Aneurysm; Angiotensin II; Animal Model; Apoptosis; Binding; Biochemical; Biology; Blood Vessels; CHI3L1 gene; Cell Adhesion; Cell Culture Techniques; Cell model; Cell physiology; Cells; Cellular Assay; Cessation of life; Chemotaxis; Chronic; Complex; Data; Development; Disease; Disease Progression; Down-Regulation; Elderly; Endothelial Cells; Event; Family suidae; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Growth; Health; Histologic; Human; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intervention; Lead; Mediating; Methods; MicroRNAs; Modeling; Molecular; Monitor; Mus; Mutagenesis; Mutate; Operative Surgical Procedures; Oxidative Stress; Pancreatic Elastase; Pathway interactions; Pharmacology; Play; Premature aging syndrome; Prevalence; Procedures; Process; Regulation; Research; Risk Factors; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Second Messenger Systems; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specificity; Stents; Structure; Therapeutic; Time; Tissues; Tobacco use; Transfection; Ultrasonography; Up-Regulation; Vascular Smooth Muscle; Veterans; age related; aged; animal tissue; base; cell type; clinical translation; cytokine; in vivo; inflammatory marker; macrophage; male; molecular modeling; monocyte; mouse model; novel; novel therapeutic intervention; older patient; overexpression; physiologic model; pre-clinical; prevent; protein expression; public health relevance; sex; success; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease of primarily older patients. While surgery and stent-grafting are highly effective in preventing death by rupture from larger AAA, they represent complex procedures with multiple potential complica-tions. Importantly, there are currently no therapeutic strategies that limit the growth of aneurysms, due in large part to a lack of understanding of the underlying molecular mechanisms of disease and progression. In addition to tobacco use, genetic predilection, and male sex, the most important risk factor for AAA is advanced age. As such, it is not surprising that over 68,000 Veterans within the VHA suffer from AAA. After age 65 years, the prevalence of AAA increases by 6% per decade. To better understand this relationship, we examined a preclinical animal model of AAA in both young and aged male mice, and observed accelerated disease formation and enhanced interleukin-6(IL6)- based inflammatory signaling with aging. We also found that miR-24 is downregulated in murine AAA models, as well as human AAA tissue. Furthermore, microarray transcriptional profiling showed that a highly significant percentage of the putative targets of miR-24 were differentially and inversely upregulated during AAA development. Additionally we found that miR-24 is downregulated by IL6 in vascular smooth muscle and macrophages in vitro. We hypothesize aging enhances IL6 signaling, leading to downregulation of vascular miR-24. Reduced activity of miR-24, in turn, is permissive for a panel of downstream inflammatory genes that play a role in aging-accelerated AAA development. Therefore, enhancing miR-24 expression and activity within the aortic wall may have therapeutic benefit. To investigate this molecular cascade, we will use pharmacological and molecular methods to delineate the signaling events initiated by IL6 in vitro that result in decreased miR-24 levels (Specific Aim 1). Next, we will elucidate the effects manipulating miR-24 levels have upon inflammatory gene expression and cellular function (Specific Aim 2). Finally, we will alter miR-24 levels in vivo to evaluate the effects upon age-accelerated AAA formation (Specific Aim 3). Completion of these specific aims will delineate a novel mechanism that may underlie age-related vascular inflammation and accelerated aneurysm formation and provide the basis for clinical translation.

描述（由申请人提供）： 腹主动脉瘤（AAA）疾病是一种常见的、致死性的、高度致命的疾病，主要发生在老年患者中。虽然手术和支架移植对于预防死亡非常有效 由于较大的 AAA 破裂，它们代表了具有多种潜在并发症的复杂手术。重要的是，目前没有限制动脉瘤生长的治疗策略，这在很大程度上是由于缺乏对疾病和进展的潜在分子机制的了解。除了吸烟、遗传倾向和男性之外，AAA 最重要的危险因素是高龄。因此，VHA 内超过 68,000 名退伍军人患有 AAA 就不足为奇了。 65 岁以后，AAA 的患病率每十年增加 6%。为了更好地理解这种关系，我们在年轻和老年雄性小鼠中检查了 AAA 的临床前动物模型，并观察到随着衰老，疾病形成加速，并且基于白细胞介素 6 (IL6) 的炎症信号传导增强。我们还发现 miR-24 在小鼠 AAA 模型以及人类 AAA 组织中下调。此外，微阵列转录分析表明，在 AAA 发育过程中，miR-24 假定靶标的很大一部分被差异性和反向上调。此外，我们发现体外血管平滑肌和巨噬细胞中 miR-24 被 IL6 下调。我们假设衰老会增强 IL6 信号传导，导致血管 miR-24 下调。 miR-24 活性的降低反过来又允许一组下游炎症基因在加速衰老的 AAA 发展中发挥作用。因此，增强主动脉壁内的 miR-24 表达和活性可能具有治疗益处。为了研究这种分子级联反应，我们将使用药理学和分子方法来描述 IL6 体外引发的信号事件，导致 miR-24 水平降低（具体目标 1）。接下来，我们将阐明操纵 miR-24 水平对炎症基因表达和细胞功能的影响（具体目标 2）。最后，我们将改变体内 miR-24 水平，以评估对年龄加速 AAA 形成的影响（具体目标 3）。这些具体目标的完成将描绘出一种可能是与年龄相关的血管炎症和加速动脉瘤形成的基础的新机制，并为临床转化提供基础。

项目成果

Nicotine Affects Murine Aortic Stiffness and Fatigue Response During Supraphysiological Cycling.

尼古丁影响超生理循环过程中小鼠主动脉僵硬和疲劳反应。

• DOI: 10.1115/1.4051706
• 发表时间: 2022
• 期刊: Journal of biomechanical engineering
• 作者: Ho,Elizabeth;Mulorz,Joscha;Wong,Jason;Wagenhäuser,MarkusU;Tsao,PhilipS;Ramasubramanian,AnandK;Lee,Sang-JoonJohn
• 通讯作者: Lee,Sang-JoonJohn