MicroRNA Regulation of Nicotine Accelerated AAAs

尼古丁加速 AAA 的 MicroRNA 调控

• 批准号: 8828778
• 负责人: Philip S Tsao
• 金额: $ 34.72万
• 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/8828778
• 关键词: 3' Untranslated Regions; Abdominal Aortic Aneurysm; Address; Adverse effects; Aneurysm; Animal Model; Apoptosis; Biological Assay; Blood Vessels; 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; base; cell behavior; cigarette smoking; cytokine; in vivo; macrophage; male; monocyte; 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）疾病是主要老年患者的常见，病态且高度致命的疾病。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 了解疾病和进展的潜在分子机制。除了高龄，遗传偏爱和男性外，AAA的最重要危险因素是烟草使用史。我们发现，将AAA的两种临床前动物模型补充与主要的烟草成分，尼古丁会导致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是促炎的，MiR-24是慢性炎症中的主要疑问，并加速了与尼古丁补充相关的AAA发育，因此可能提供治疗靶标。我们假设尼古丁会导致主动脉miR-24的下调，从而导致与炎症和加速AAA疾病有关的基因表达升高。相反，增强主动脉壁内的miR-24表达和活性将具有治疗益处。在特定的目标1中，我们将使用细胞培养模型以及药理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。在特定的目标2中，我们将确定MiR-24降低对呼吸症基因表达和细胞功能的下游影响。最后，在特定的目标3中，我们将在体内调节miR-24水平，以评估对AAA形成的影响。这些具体目的将研究一种新的机制，该机制可能是尼古丁引起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翻译提供了基础。