MicroRNA Regulation of Nicotine Accelerated AAAs

尼古丁加速 AAA 的 MicroRNA 调控

• 批准号: 9249630
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249630
• 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; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Elderly; Evaluation; Event; Gene Expression; Gene Proteins; Gene Targeting; Genetic; Genetic Transcription; Growth; Histologic; Human; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; MAPK3 gene; Mediating; Methods; MicroRNAs; Modeling; Molecular; Molecular Models; Monitor; Mus; Muscle Cells; Mutagenesis; Mutation; Nicotine; Operative Surgical Procedures; Oxidative Stress; Pharmacology; 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; Ultrasonography; Vascular Endothelial Cell; Vascular Smooth Muscle; cell behavior; cigarette smoking; clinical translation; cytokine; in vivo; macrophage; male; molecular modeling; monocyte; mouse model; novel; older patient; overexpression; physiologic model; pre-clinical; prevent; public health relevance; 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、病态的和高度致命的疾病，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、遗传倾向和男性外，AAA最重要的风险因素是吸烟史。我们发现，两种临床前AAA动物模型补充主要烟草成分尼古丁，会加速疾病形成和增强炎症信号。这些效应与microRNA(MiR)-24的下调有关。鉴于它的许多基因靶点是促炎的，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表达下调，导致炎症相关基因表达上调，并加速AAA疾病。相反，增强miR-24在主动脉壁内的表达和活性将有治疗上的好处。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水平下降的信号事件。在特定的目标2中，我们将确定降低miR-24对炎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的水平，以评估其对AAA形成的影响。这些特定的目的将探索一种新的机制，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翻译提供基础。

项目成果

H19 Induces Abdominal Aortic Aneurysm Development and Progression.

• DOI: 10.1161/circulationaha.117.032184
• 发表时间: 2018-10-09
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Li DY;Busch A;Jin H;Chernogubova E;Pelisek J;Karlsson J;Sennblad B;Liu S;Lao S;Hofmann P;Bäcklund A;Eken SM;Roy J;Eriksson P;Dacken B;Ramanujam D;Dueck A;Engelhardt S;Boon RA;Eckstein HH;Spin JM;Tsao PS;Maegdefessel L
• 通讯作者: Maegdefessel L

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

• DOI: 10.1371/journal.pone.0149288
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Azuma J;Wong RJ;Morisawa T;Hsu M;Maegdefessel L;Zhao H;Kalish F;Kayama Y;Wallenstein MB;Deng AC;Spin JM;Stevenson DK;Dalman RL;Tsao PS
• 通讯作者: Tsao PS

Non-coding RNAs in aneurysmal aortopathy.

动脉瘤性主动脉病中的非编码 RNA。

• DOI: 10.1016/j.vph.2018.06.008
• 发表时间: 2019
• 期刊: Vascular pharmacology
• 影响因子: 4
• 作者: Spin,JoshuaM;Li,DanielY;Maegdefessel,Lars;Tsao,PhilipS
• 通讯作者: Tsao,PhilipS