MicroRNA Regulation of Nicotine Accelerated AAAs

尼古丁加速 AAA 的 MicroRNA 调控

• 批准号: 9043180
• 负责人: Philip S Tsao
• 金额: $ 35.25万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043180
• 关键词: 3' Untranslated Regions; Abdominal Aortic Aneurysm; Address; Adverse effects; Aneurysm; Animal Model; Apoptosis; Biological Assay; Blood Vessels; CHI3L1 gene; Cell Adhesion; Cell Culture Techniques; Cell physiology; Cells; Cessation of life; Chemotaxis; Chronic; Clinical; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Elderly; Evaluation; Event; Gene Expression; Gene Proteins; Gene Targeting; Genetic; Growth; Health; Human; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; MAPK3 gene; Mediating; Methods; MicroRNAs; Modeling; Molecular; Monitor; Mus; Mutagenesis; Mutation; Nicotine; Operative Surgical Procedures; Oxidative Stress; Physiological; Procedures; Reactive Oxygen Species; Recording of previous events; Regulation; Repression; Risk Factors; Role; Rupture; Second Messenger Systems; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specificity; Stents; Structure; Supplementation; Therapeutic; Time; Tissues; Tobacco; Tobacco use; Translations; Ultrasonography; Vascular Endothelial Cell; Vascular Smooth Muscle; base; cell behavior; cigarette smoking; cytokine; in vivo; macrophage; male; monocyte; mouse model; novel; older patient; overexpression; pre-clinical; prevent; second messenger; sex; 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. 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.

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。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 了解疾病和进展的潜在分子机制。除了高龄、遗传倾向和男性之外，AAA 最重要的危险因素是吸烟史。我们发现，在两种 AAA 临床前动物模型中补充主要烟草成分尼古丁，会加速疾病形成并增强炎症信号传导。这些影响与 microRNA (miR)-24 的下调有关。鉴于其许多基因靶标具有促炎性，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。我们假设尼古丁会导致主动脉 miR-24 下调，导致与炎症相关的基因表达升高并加速 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信号事件，从而导致 miR-24 水平降低。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。这些具体目标将研究可能是尼古丁诱导的血管炎症和加速动脉瘤形成的新机制，并为推进未来的研究和临床转化提供基础。