A Novel Therapy For Preeclampsia

先兆子痫的新疗法

• 批准号: 10198998
• 负责人: Eric Matthew George
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198998
• 关键词: Affect; Affinity; Angiogenic Proteins; Animal Model; Attention; Attenuated; Binding; Biological; Birth; Blood; Blood Circulation; Brain Hypoxia-Ischemia; Cardiovascular system; Carrier Proteins; Chronic; Clinical; Data; Disease; Drug Carriers; Drug Kinetics; Eclampsia; Elastin; Endothelial Growth Factors Receptor; Epidemiology; Etiology; Event; Family member; Fetal Growth Retardation; Fetal safety; Fetus; Half-Life; Health; Hour; Hypertension; In Vitro; Induced Labor; Infant; Intervention; Ischemia; KDR gene; Kidney; Lead; Life; Maternal-Fetal Exchange; Modeling; Monitor; Morbidity - disease rate; Mothers; Outcome; PGF gene; Pathogenicity; Pathologic; Pathway interactions; Patients; Peptides; Perfusion; Perinatal mortality demographics; Pharmacological Treatment; Placenta; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Premature Birth; Prophylactic treatment; Proteins; Proteinuria; Rattus; Renal function; Research; Risk; Rodent Model; Safety; Seizures; Signal Transduction; Stream; Symptoms; Teratogens; Testing; Therapeutic; Treatment Efficacy; United States; Uterus; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Virulence Factors; Woman; associated symptom; base; cardiovascular disorder risk; effective therapy; endothelial dysfunction; fetal; hypoperfusion; improved; in vivo; maternal hypertension; maternal morbidity; mortality; novel; novel therapeutics; offspring; perinatal morbidity; polypeptide; pre-clinical; pregnancy disorder; pregnancy hypertension; prenatal exposure; pressure; receptor; release factor; response; safety study; side effect; synthetic peptide; synthetic protein; therapeutic protein; therapeutically effective

Preeclampsia remains a major health concern, affecting 5-10% of all pregnancies in the United States. It is a leading cause of maternal and perinatal morbidity and mortality. Currently, there is no effective therapy for the management of the preeclamptic patient, with the disease only remitting after birth. While the underlying mechanisms are not clear, it is believed that inadequate remodeling of the maternal vasculature leads to placental hypo-perfusion, resulting in chronic placental hypoxia/ischemia. In response the placenta releases pathogenic factors into the maternal blood stream, leading to widespread maternal endothelial dysfunction and hypertension. In recent years, a great deal of attention has been focused on the secretion of an anti- angiogenic protein, the fms-like tyrosine kinase-1 (sFlt-1). Despite intensive research into this pathogenic pathway, no therapeutics have emerged which can adequately target sFlt-1 in the preeclampsia patient. In this proposal, we describe a novel therapeutic protein which consists of placental growth factor (PlGF), a VEGF family member specific for Flt-1, fused to the synthetic protein carrier Elastin Like Polypeptide (ELP), which we have recently demonstrated restricts attached therapeutics to the maternal compartment improving fetal safety during administration. We hypothesize that ELP-PlGF will attenuate the maternal and fetal complications associated with placental insufficiency, and may therefore be a potential therapeutic for the management of preeclampsia. This proposal will study the safety and efficacy of this therapeutic in a relevant preclinical animal model of preeclampsia.

先兆子痫仍然是一个主要的健康问题，影响美国所有怀孕的5-10%。这是一个 产妇和围产期发病率和死亡率的主要原因。目前，没有有效的治疗方法， 先兆子痫患者的管理，疾病仅在出生后缓解。虽然底层 机制尚不清楚，但据信母体脉管系统的不充分重塑导致 胎盘灌注不足，导致慢性胎盘缺氧/缺血。作为回应， 致病因子进入母体血流，导致广泛的母体内皮功能障碍， 高血压近年来，大量的注意力集中在抗- 血管生成蛋白，fms样酪氨酸激酶-1（sFlt-1）。尽管深入研究了这种致病性 尽管sFlt-1与sFlt-1通路相关，但尚未出现可充分靶向先兆子痫患者中的sFlt-1的治疗剂。在这 建议，我们描述了一种新的治疗性蛋白质，它由胎盘生长因子（PlGF），VEGF Flt-1家族成员，融合到合成蛋白载体弹性蛋白样多肽（ELP），我们 最近已经证明将附加治疗剂限制在母体隔室， 给药期间。我们假设ELP-PlGF将减轻母体和胎儿并发症 与胎盘功能不全相关，因此可能是一种潜在的治疗方法， 先兆子痫该提案将在相关的临床前研究中研究这种治疗剂的安全性和有效性。 先兆子痫的动物模型。

项目成果

Animal Models of Preeclampsia: Mechanistic Insights and Promising Therapeutics.

• DOI: 10.1210/endocr/bqac096
• 发表时间: 2022-08-01
• 期刊: Endocrinology
• 影响因子: 4.8

Immunological comparison of pregnant Dahl salt-sensitive and Sprague-Dawley rats commonly used to model characteristics of preeclampsia.

妊娠 Dahl 盐敏感大鼠和常用于模拟先兆子痫特征的 Sprague-Dawley 大鼠的免疫学比较。

• DOI: 10.1152/ajpregu.00298.2020
• 发表时间: 2021
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Taylor,ErinB;George,EricM;Ryan,MichaelJ;Garrett,MichaelR;Sasser,JenniferM
• 通讯作者: Sasser,JenniferM