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）疾病是主要老年患者的常见，病态和高度致命的疾病。而手术和支架治疗在预防死亡方面非常有效 通过较大的AAA破裂，它们代表具有多个潜在复杂性的复杂程序。重要的是，目前尚无治疗策略可以限制动脉瘤的生长，这在很大程度上是由于缺乏对疾病和进展的基本分子机制的了解。除了使用烟草，遗传偏好和男性外，AAA的最重要危险因素是高龄。因此，VHA内有68,000多名退伍军人遭受了AAA的困扰也就不足为奇了。 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，我们检查了年轻和老年小鼠中AAA的临床前动物模型，并观察到了加速的疾病形成，并增强了天介素-6（IL6）的基于老化的炎症信号传导。我们还发现，在鼠AAA模型以及人AAA组织中，miR-24被下调。此外，微阵列的转录分析表明，在AAA发育过程中，miR-24的假定靶标的高度显着，并反向上调。此外，我们发现在体外血管平滑肌和巨噬细胞中，miR-24被IL6下调。我们假设衰老增强了IL6信号传导，导致血管miR-24的下调。 MiR-24的活性降低反过来允许一组下游炎症基因，这些炎症基因在衰老的AAA发育中发挥作用。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，我们将使用药理学和分子方法来描述IL6在体外引发的信号事件，从而导致miR-24水平降低（特定目标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（特定目标2）。最后，我们将在体内改变miR-24水平，以评估对年龄加速AAA形成的影响（特定的目标3）。这些特定目标的完成将描述一种新的机制，该机制可能是与年龄有关的血管炎症的基础，并加速了动脉瘤形成，并为临床翻译提供了基础。

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