Prostanoid-dependent abdominal aortic aneurysm formation

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，环氧化酶-2 （COX-2）的遗传或药理学失活可降低长期注射血管紧张素II （Angll）的小鼠AAAs的发生率和严重程度。此外，与未受累主动脉相比，AAAs中COX-2的表达显著增加。我们的初步研究还表明，PGE2受体EP4在动脉瘤组织中的表达显著增加。然而，前列腺素受体在AAA形成中的作用尚不明确。本建议的长期目标是阐明前列腺素促进AAAs的机制。我们提出COX-2通过优先合成分别特异性激活EP4和TP受体的PGE2和TXA2参与Angll诱导的AAA发育的所有阶段的假设。这一假设基于先前的观察：a)人类AAAs外植体培养物表达显著水平的COX-2。b) PGE2通过增加基质金属蛋白酶的表达和/或激活以及诱导平滑肌细胞凋亡参与血管病理。c) TXA2增加粘附分子表达，促进巨噬细胞向血管壁内流。因此，我们提出以下具体目标：1)确定COX-2在AAA形成的多个阶段中的作用。这些研究将使用COX-2基因缺陷的小鼠以及COX-2特异性抑制剂塞来昔布。2)确定前列腺素受体EP4和TP基因缺失对AAA形成的影响。这些研究将提供cox -2依赖性前列腺素作用的机制观点，并将为AAAs的新治疗方法的发展提供见解。本研究的目的是寻找腹主动脉瘤（AAAs）的新治疗方法。AAAs是一种危及生命的疾病，大约有5%的65岁以上的男性患有这种疾病，一旦这种疾病形成，主动脉破裂的可能性就会增加，而大多数人都无法存活。人类主动脉瘤的病因尚不清楚，但被认为与主动脉壁内的炎症有关。因此，我们将使用这种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，因为它们将有助于确定人类这种疾病的非手术治疗方法。

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.