Prostanoid-dependent abdominal aortic aneurysm formation

前列腺素依赖性腹主动脉瘤形成

• 批准号: 7413673
• 负责人: Charles David Loftin
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413673
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Angiotensin II; Animal Disease Models; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Aortic Aneurysm; Apoptosis; Arachidonic Acids; Attenuated; Binding; Biological; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Chronic; Data; Development; Dinoprostone; Disease; Disease regression; EP4 receptor; Effectiveness; Elderly; Event; Genetic; Health; Human; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Life; Matrix Metalloproteinases; Mediating; Messenger RNA; Metabolic; Modeling; Mus; Operative Surgical Procedures; Pathology; Pharmaceutical Preparations; Pharmacological Treatment; Play; Population; Prostaglandin E Receptor; Prostaglandin H2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Reporting; Research Personnel; Role; Rupture; Severities; Smooth Muscle Myocytes; Staging; Stimulus; Testing; Thinking; Thromboxane A2; Thromboxane Receptor; Tissues; Wild Type Mouse; Work; abdominal aorta; aging population; base; celecoxib; chemokine; cyclooxygenase 1; cyclooxygenase 2; human WFDC2 protein; inhibitor/antagonist; insight; interest; macrophage; male; monocyte; novel therapeutics; programs; receptor; response

DESCRIPTION (provided by applicant): Our recent report together with our preliminary studies show that genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) reduces the incidence and severity of AAAs in mice chronically infused with angiotensin II (Angll). Furthermore, significant COX-2 expression is increased in AAAs as compared to the uninvolved aorta. Our preliminary studies also show that the expression of the PGE2 receptor EP4 is significantly increased in aneurysmal tissue. However, the role of the prostanoid receptors in AAA formation is not clearly defined. The long-term objectives of this proposal are to elucidate mechanisms by which prostanoids contribute to AAAs. We propose the hypothesis that COX-2 participates in all stages of Angll- induced AAA development through preferential synthesis of PGE2 and TXA2 which specifically activate EP4 and TP receptors, respectively. This hypothesis is based on previous observations that a) Explant cultures from human AAAs express significant levels of COX-2. b) PGE2 contributes to vascular pathology by increasing expression and/or activation of matrix metalloproteinases and inducing smooth muscle cell apoptosis. c) TXA2 increases adhesion molecule expression and contributes to influx of macrophages in the vessel wall. Therefore, we propose the following specific aims: 1) Determine the role of COX-2 at multiple stages of AAA formation. These studies will use mice genetically deficient in COX-2 as well as the COX-2- specific inhibitor, celecoxib. 2) Determine the effect of genetic deficiency of the prostanoid receptors, EP4 and TP, on AAA formation. These studies will provide a mechanistic view of the role of COX-2-dependent prostanoids, and will provide insight into the development of novel therapeutics for AAAs. The objectives of the proposed studies are to identify new treatments for abdominal aortic aneurysms (AAAs). AAAs are a life-threatening disease which afflict approximately 5% of the male population over the age of 65, and once the disease has formed, there is an increased chance for rupture of the aorta, an event which most people do not survive. The cause of aortic aneurysms in humans is not known but is thought to involve inflammation within the wall of the aorta. Therefore, we will use an animal model of this disease to determine the mechanisms by which this disease occurs in humans. These studies are important as they will help identify non-surgical treatments for this disease in humans.

描述（由申请人提供）：我们最近的报告以及我们的初步研究表明，环氧合酶-2（COX-2）的遗传或药理失活降低了在长期注入血管紧张素II（ANGLL）的小鼠中AAA的发生率和严重性。此外，与未参与主动脉相比，AAA中有明显的COX-2表达增加。我们的初步研究还表明，在动脉瘤组织中PGE2受体EP4的表达显着增加。然而，未明确定义前列腺素受体在AAA形成中的作用。该提案的长期目标是阐明前列腺素对AAAS贡献的机制。我们提出了以下假设：COX-2通过优先合成PGE2和TXA2，分别专门激活EP4和TP受体，参与了AAA诱导的AAA发育的所有阶段。该假设基于以前的观察结果，即A）来自人类AAAS的外植物表达了大量的COX-2。 b）PGE2通过增加表达和/或激活基质金属蛋白酶并诱导平滑肌细胞凋亡而导致血管病理。 c）TXA2增加了粘附分子的表达，并有助于血管壁中巨噬细胞的流入。因此，我们提出以下特定目的：1）确定COX-2在AAA组的多个阶段的作用。这些研究将使用遗传上COX-2以及COX-2-特异性抑制剂Celecoxib的小鼠。 2）确定前列腺素受体EP4和TP的遗传缺乏对AAA形成的影响。这些研究将提供有关COX-2依赖性前列腺素的作用的机械观点，并将提供对AAAS新型疗法发展的见解。拟议研究的目标是确定腹主动脉瘤（AAAS）的新疗法。 AAAS是一种威胁生命的疾病，折磨于65岁以上男性人群的约5％，一旦疾病形成，主动脉破裂的可能性就会增加，这是大多数人无法生存的事件。人类主动脉瘤的原因尚不清楚，但被认为涉及主动脉壁内的炎症。因此，我们将使用该疾病的动物模型来确定这种疾病在人类中发生的机制。这些研究很重要，因为它们将有助于鉴定人类中这种疾病的非手术治疗。