Prevention of Preeclampsia-associated preterm births

预防先兆子痫相关的早产

• 批准号: 8780971
• 负责人: SHEAU-YU Teddy HSU
• 金额: $ 22.5万
• 依托单位: ADEPTHERA, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780971
• 关键词: Affect; Agonist; Angiogenic Factor; Animal Model; Animals; Antihypertensive Agents; Birth; Blood Circulation; Blood Vessels; Cardiovascular system; Caring; Cessation of life; Defect; Development; Disease; Drug Kinetics; Edema; Endocrine system; Equilibrium; Exhibits; Face; Fetal Growth Retardation; Fetus; Gestational Age; Goals; Hormonal Change; Hormones; Human; Hypertension; Investigation; Investigational Drugs; Lead; Life; Maternal-Fetal Exchange; Medical; Modeling; Morbidity - disease rate; Neonatal; Nitric Oxide Synthase; Organ failure; Patients; Peripheral Resistance; Phase; Placenta; Play; Pre-Eclampsia; Pregnancy; Premature Birth; Premature Infant; Prevention; Proteinuria; RAMP1; Rattus; Receptor Signaling; Regulation; Rodent Model; Role; Seizures; Small Business Innovation Research Grant; Staging; Symptoms; Testing; Therapeutic; Tissues; Toxicology; United States; United States Food and Drug Administration; Vascular Diseases; adrenomedullin; analog; base; cost; design; drug candidate; endothelial dysfunction; fetal; fetal blood; glomerular function; improved; in vivo; inhibitor/antagonist; meetings; mortality; novel; novel therapeutics; pre-clinical; pregnant; prevent; protective effect; public health relevance; receptor

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.

描述（由申请人提供）：先兆子痫是一种妊娠期特有的高血压疾病，影响 5-8% 的妊娠。这种疾病可导致多器官衰竭、癫痫发作和孕产妇死亡。在美国，先兆子痫也是造成 20% 早产的原因。尽管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，预防婴儿先兆子痫相关不良影响的最佳方法是推迟早产。不幸的是，目前的治疗对于大多数先兆子痫患者来说无法有效地将分娩延迟几天以上。尽管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性疾病，涉及母胎界面缺陷以及母体血管功能障碍。这些缺陷可能导致全身内皮功能障碍。结果，母婴血液循环受到限制，导致高血压、蛋白尿和胎儿生长迟缓。最近的发现表明，一组血管受体 CLR/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发挥着至关重要的作用。重要的是，研究表明，阻断 CLR/RAMP 受体信号传导会导致动物模型中出现类似先兆子痫的症状，而这些 CLR/RAMP 受体激动剂可以减轻在妊娠晚期接受一氧化氮合酶抑制剂预处理的动物的类似先兆子痫的症状。因此，药物激活 CLR/RAMP 受体信号传导可能是治疗先兆子痫患者高血压、蛋白尿和胎儿生长迟缓并降低早产可能性的有前途的方法。我们的目标是研究一组新型 CLR/RAMP 受体激动剂在先兆子痫大鼠模型中的保护作用，这些激动剂在体内具有有效的抗高血压作用。成功证明这些新候选药物的功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。