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

描述(由申请人提供)： 腹主动脉瘤(AAA)是一种常见、致命性高的疾病，主要发生在老年患者。而手术和支架移植在预防死亡方面是非常有效的 由于较大的AAA破裂，它们代表了具有多个潜在并发症的复杂过程。重要的是，目前还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、遗传倾向和男性性别外，AAA最重要的风险因素是高龄。因此，VHA内超过68,000名退伍军人患有AAA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，我们研究了年轻和老年雄性小鼠的AAA临床前动物模型，并观察了随着年龄的增长，疾病形成的加速和基于白细胞介素6(IL6)的炎症信号的增强。我们还发现miR-24在小鼠AAA模型以及人AAA组织中下调。此外，微阵列转录图谱显示，在AAA发育过程中，miR-24的假定靶点中有非常显著的比例差异和反向上调。此外，我们还在体外发现IL6下调了miR-24在血管平滑肌和巨噬细胞中的表达。我们假设衰老增强IL6信号，导致血管miR-24下调。反过来，miR-24活性降低对一组下游炎症基因是允许的，这些基因在衰老加速的AAA发展中发挥作用。因此，增强miR-24在主动脉壁内的表达和活性可能具有治疗作用。为了研究这一分子级联反应，我们将使用药理学和分子方法来描述IL6在体外启动的导致miR-24水平下降的信号事件(特定目标1)。接下来，我们将阐明操纵miR-24水平对炎性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，以评估其对年龄加速的AAA形成的影响(特定目标3)。这些特定目标的完成将勾勒出一种新的机制，可能是年龄相关性血管炎症和加速动脉瘤形成的基础，并为临床翻译提供基础。

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.