Mentored Patient-Oriented Research Career Development Aw

(改编自申请人的摘要)：PPH是一种高度 发病率和死亡率主要发生在年轻成年妇女中。这个 这种疾病的病因尚不清楚，但产量增加 血栓素A(2)[TXA(2)]与前列环素合成减少 [前列腺素I]为发病机制提供线索。在过去的十年里， 静脉注射前列腺素，前列环素的合成类似物，已经出现 被认为是治疗PPH最有效的方法。然而，对 依前列烯醇存在于大多数需要进展性治疗的患者中 剂量递增以维持疗效。此外，只有70%的患者 从治疗中受益。来自临床研究的初步数据 产后增生症患者显示环前列烯醇可增加循环水平 血管紧张素II(AII)，一种有效的血管收缩和平滑肌有丝分裂原， 它可以刺激纤溶酶原激活物抑制物1(PAI-1)的产生 1)、促凝血蛋白和血管内皮生长因子(VEGF)， 通透性和血管生成生长因子。 这项提议将探索两个假设：1)肾素激活- 血管紧张素系统(RAS)在慢性给药中的作用 剂量需求增加的原因；2)RAS的直接和间接影响 活化和持续的TXA(2)产生限制了临床疗效 依波前列烯醇。为了评估这些假设，申请人将：a)描述 环前列烯醇诱导的RAS激活与比较 右心血流动力学数据的生化变化 导尿术；b)描述通过测量 距离步行6分钟，楔子获得结构变化 肺循环的血管造影术；以及c)在合作中确定 与其他医疗中心研究，是否同时治疗和 血管紧张素转换酶抑制剂将提高心力衰竭的临床疗效 依波前列烯醇和预防慢性剂量增加的需要。这些研究 将促进我们对环前列烯醇的作用机制的了解 肺动脉高压。

(Adapted from the applicant's abstract): PPH is a disease of high morbidity and mortality occurring predominately in young adult women. The etiology of this illness remains unknown, but increased production of thromboxane A(2) [TxA(2)] and decreased synthesis of prostacyclin [prostaglandin I] provide clues to the pathogenesis. Over the past decade, intravenous epoprostenol, the synthetic analogue of prostacyclin, has emerged as the most effective treatment of PPH. However, tolerance to the effects of epoprostenol occurs in the majority of patients necessitating progressive dose escalation to maintain efficacy. Furthermore, only 70% of patients benefit from treatment. Preliminary data derived from clinical studies of patients with PPH demonstrate that epoprostenol increases circulating levels of angiotensin II (AII), a potent vasoconstrictor and smooth muscle mitogen, which can stimulate production of both plasminogen activator inhibitor 1 (PAI- 1), a procoagulant protein, and vascular endothelial growth factor (VEGF), permeability and angiogenic growth factor. This proposal will explore two hypotheses: 1) activation of the renin- angiotensin system (RAS) during chronic administration of epoprostenol is the cause of increasing dose requirements; 2) direct and indirect effects of RAS activation and persistent TxA(2) production limit the clinical efficacy of epoprostenol. To evaluate these hypotheses, the applicant will: a) delineate the relationship between epoprostenol-induced RAS activation and compare biochemical changes with hemodynamic data obtained during right heart catheterization; b) delineate clinical data obtained from measurement of distance walked in six minutes, and structural changes obtained by wedge angiography of pulmonary circulation; and c) determine, in a collaborative study with other medical centers, whether concomitant treatment with and angiotensin converting enzyme inhibitor will improve the clinical efficacy of epoprostenol and prevent the need for chronic dose escalation. These studies will advance our knowledge of the mechanism of action of epoprostenol and pulmonary hypertension.