MicroRNA Regulation of Nicotine Accelerated AAAs

描述（由申请方提供）：腹主动脉瘤（AAA）疾病是一种常见的、病态的、高致死性疾病，主要发生在老年患者中。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足够的药物。 了解疾病和进展的潜在分子机制。除了高龄、遗传偏好和男性外，AAA最重要的风险因素是吸烟史。我们已经发现，用主要烟草成分尼古丁补充AAA的两种临床前动物模型会加速疾病形成并增强炎症信号。这些作用与microRNA（miR）-24的下调有关。鉴于其许多基因靶点是促炎性的，miR-24是与尼古丁补充相关的慢性炎症和加速AAA发展的主要嫌疑人，因此可能提供治疗靶点。我们假设尼古丁导致主动脉miR-24下调，导致炎症相关基因表达升高，加速AAA疾病。相反，增强主动脉壁内的miR-24表达和活性将具有治疗益处。在具体目标1中，我们将使用细胞培养模型以及药理学和分子方法来描述尼古丁引发的导致miR-24水平降低的信号传导事件。在具体目标2中，我们将确定减少的miR-24对炎症基因表达和细胞功能的下游影响。最后，在具体目标3中，我们将在体内调节miR-24水平，以评估对AAA形成的影响。这些特定的目标将研究一种新的机制，这种机制可能是尼古丁诱导的血管炎症和加速动脉瘤形成的基础，并为推进未来的研究和临床转化提供基础。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease of primarily older patients. 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 advanced age, genetic predilection, and male sex, the most important risk factor for AAA is a history of tobacco use. We have found that supplementation of two preclinical animal models of AAA with the major tobacco component, nicotine, causes accelerated disease formation and enhanced inflammatory signaling. These effects are associated with downregulation of microRNA (miR)-24. Given that many of its gene targets are pro-inflammatory, miR-24 is a prime suspect in the chronic inflammation and accelerated AAA development associated with nicotine supplementation and may, therefore, offer a therapeutic target. We hypothesize that nicotine causes downregulation of aortic miR-24, resulting in elevated expression of genes related to inflammation and accelerated AAA disease. Conversely, enhancing miR-24 expression and activity within the aortic wall will have therapeutic benefit. In Specific Aim 1, we will use cell culture models as well as pharmacological and molecular methods to delineate the signaling events initiated by nicotine that result in decreased miR-24 levels. In Specific Aim 2, we will determine the downstream effects of reduced miR-24 on inflamamtiory gene expression and cellular function. Finally, in Specific Aim 3, we will modulate miR-24 levels in vivo to evaluate the effects upon AAA formation. These specific aims will investigate a novel mechanism that may underlie nicotine-induced vascular inflammation and accelerated aneurysm formation as well as provide the basis for advancing future research and clinical translation.