Prevention of Preeclampsia-associated preterm births

描述（由申请人提供）：先兆子痫是一种妊娠特异性高血压疾病，影响5-8%的妊娠。这种疾病可导致多器官衰竭、癫痫发作和产妇死亡。在美国，先兆子痫也是造成多达20%早产的原因。虽然更好的新生儿护理提高了早产儿存活的可能性，但许多早产儿面临着死亡率上升和严重的长期发病率。医学专家一致认为，预防婴儿不良先兆子痫相关影响的最佳方法是推迟早产。不幸的是，目前的治疗在大多数先兆子痫患者中延迟分娩超过几天是无效的。虽然先兆子痫的病因尚不清楚，但已提出先兆子痫是一种两阶段疾病，其涉及母胎界面的缺陷以及母体血管功能障碍。这些缺陷可能导致全身性内皮功能障碍。结果，母胎血液循环受到限制，导致高血压、蛋白尿和胎儿发育迟缓。最近的发现表明，一组血管受体，RAMP/RAMP受体，在妊娠期间胎儿-胎盘组织的发育和血管紧张素调节中起关键作用。重要的是，已经表明阻断NAT 3/RAMP受体信号传导导致动物模型中的先兆子痫样症状，并且NAT 3/RAMP受体的那些激动剂可以抑制在妊娠晚期期间用一氧化氮合酶抑制剂预处理的动物中的先兆子痫样症状。因此，药理学激活的ESTA/RAMP受体信号传导可能是一个有前途的方法来治疗高血压，蛋白尿，和胎儿生长迟缓先兆子痫患者，并减少早产的可能性。我们的目的是研究一组格鲁新型的β-受体/RAMP受体激动剂在先兆子痫大鼠模型中的保护作用，这些受体激动剂在体内具有有效的抗高血压作用。成功证明这些新型候选药物的疗效将验证我们的先导化合物的进一步开发，并促进2期SBIR研究中GLP药代动力学和毒理学研究的设计。

DESCRIPTION (provided by applicant): Preeclampsia is a pregnancy-specific, hypertensive disorder that affects 5-8% of pregnancies. This disorder can lead to multi-organ failure, seizure, and maternal death. Preeclampsia is also responsible for as many as 20% of premature births in the United States. Although better neonatal care has improved the likelihood of preterm babies surviving, many face increased mortality and serious long-term morbidities. Medical experts agree that the best approach to prevent adverse preeclampsia-associated effects in babies is to delay premature birth. Unfortunately, current treatments are ineffective at delaying labor by more than a couple of days in the majority of preeclampsia patients. Although the cause of preeclampsia remains unclear, preeclampsia has been proposed to be a two-stage disease, which involves defects at the maternal-fetal interface as well as maternal vascular dysfunction. These defects could lead to systemic endothelial dysfunction. As a result, maternal-fetal blood circulation is restricted, leading to high blood pressure, proteinuria, and fetal growt retardation. Recent discoveries have shown that a group of vascular receptors, CLR/RAMP receptors, play crucial roles in the development of feto- placental tissues and vasotone regulation during pregnancy. Importantly, it has been shown that blocking CLR/RAMP receptor signaling leads to preeclampsia-like symptoms in animal models, and those agonists for CLR/RAMP receptors can dampen preeclampsia-like symptoms in animals that have been pretreated with a nitric-oxide-synthase inhibitor during late pregnancy. Therefore, pharmacological activation of CLR/RAMP receptor signaling could be a promising approach to treat hypertension, proteinuria, and fetal growth retardation in preeclampsia patients, and to reduce the likelihood of preterm birth. Our goal is to investigate the protective effects of a grou of novel CLR/RAMP receptor agonists, which have potent anti-hypertensive effects in vivo, in a preeclamptic rat model. Successful demonstration of the efficacy of these novel drug candidates would validate our lead compounds for further development, and facilitate the design of GLP pharmacokinetic and toxicology studies in the Phase 2 SBIR investigation.