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，环氧合酶-2（考克斯-2）的遗传或药理学失活可降低长期输注血管紧张素II（AngII）的小鼠中AAA的发生率和严重程度。此外，与未受累的主动脉相比，AAA中的考克斯-2表达显著增加。我们的初步研究还表明，前列腺素E2受体EP 4的表达显着增加，在血管平滑肌组织。然而，前列腺素受体在AAA形成中的作用尚不清楚。该提案的长期目标是阐明前列腺素类化合物促进AAAs的机制。我们提出这样的假设，即考克斯-2通过分别特异性激活EP 4和TP受体的PGE 2和TXA 2的优先合成参与AngII诱导的AAA发展的所有阶段。该假设基于先前的观察结果，即a）来自人AAA的外植体培养物表达显著水平的考克斯-2。B）PGE 2通过增加基质金属蛋白酶的表达和/或活化并诱导平滑肌细胞凋亡而促成血管病理学。c）TXA 2增加粘附分子表达并有助于巨噬细胞流入血管壁。因此，我们提出以下具体目标：1）确定考克斯-2在AAA形成的多个阶段的作用。这些研究将使用考克斯-2基因缺陷的小鼠以及考克斯-2特异性抑制剂塞来昔布。2)确定前列腺素受体EP 4和TP的遗传缺陷对AAA形成的影响。这些研究将提供考克斯-2依赖性前列腺素类作用的机制观点，并将提供对AAAs新疗法开发的深入了解。拟定研究的目的是确定腹主动脉瘤（AAA）的新治疗方法。AAA是一种危及生命的疾病，大约5%的65岁以上的男性患有这种疾病，一旦这种疾病形成，主动脉破裂的机会就会增加，大多数人都无法存活。人类主动脉瘤的原因尚不清楚，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.