Mechanisms of Cardiorenal Disease following Preeclampsia

先兆子痫后心肾疾病的机制

• 批准号: 9213459
• 负责人: Jennifer M Sasser
• 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: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213459
• 关键词: Address; Adoptive Transfer; Affect; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biochemical; Biological Availability; Blood Pressure; Blood Vessels; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Chronic Kidney Failure; Clinical; Clinical Research; Dahl Hypertensive Rats; Data; Developing Countries; Development; Diet; Disease; Endothelin-1; Exhibits; Experimental Animal Model; Experimental Models; Female; Fetal Growth Retardation; Goals; Heart Diseases; Helper-Inducer T-Lymphocyte; Human; Hypertension; Immune Cell Activation; Immune system; Inflammatory Response; Injury; Interleukin-10; Intervention; Kidney; Kidney Diseases; Knowledge; Modeling; Molecular; Morbidity - disease rate; Mothers; Nitric Oxide; Operative Surgical Procedures; Outcome; Pathogenesis; Perinatal; Perinatal Care; Pharmacology; Physiological; Placenta; Plasma; Postpartum Period; Pre-Eclampsia; Pregnancy; Production; Proteinuria; Publishing; Rattus; Recording of previous events; Regimen; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; Sodium Chloride; Stroke; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic; Treatment Protocols; United States; Woman; Work; blood pressure regulation; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; cytokine; disorder risk; endothelial dysfunction; experience; experimental study; fetal; genetic manipulation; human disease; immune activation; improved; improved outcome; inhibitor/antagonist; maternal morbidity; mortality; new therapeutic target; novel; preclinical study; pregnant; prevent; salt sensitive; therapeutic target

Preeclampsia is one of the leading causes of maternal morbidity and death worldwide today, affecting approximately 5% of all pregnancies in the United States. Preeclampsia is characterized by hypertension during the second half of pregnancy and progressive development of proteinuria, along with systemic endothelial dysfunction. The risk to the mother does not end with delivery of the fetoplacental unit however. Women who experience preeclampsia have a heightened risk for hypertension, stroke, heart disease, and kidney disease, but the mechanisms that contribute to cardiovascular and renal disease following preeclampsia are unclear. Therefore, there is a vital need for the determination of optimal therapeutic regimens for women following preeclampsia. Unfortunately, the lack of a spontaneous animal model of preeclampsia has been an obstacle in the identification of the mechanisms and potential therapeutic targets during and following preeclampsia. Our exciting preliminary data show that the Dahl Salt Sensitive (Dahl S) rat spontaneously develops characteristics of preeclampsia during pregnancy that are similar to the human disease and has accelerated cardiorenal disease and immune activation that persists postpartum. This model will allow us to significantly advance our knowledge by examining the long-term impact of preeclamptic pregnancy on endothelial function, progression of kidney disease, and immune activation in females with pre-existing hypertension and determine if intensive perinatal management of blood pressure will improve long term cardiovascular health outcomes. This project will test the central hypothesis that preeclampsia results in a lasting postpartum immunological activation that predisposes the mother to progression of endothelial dysfunction and CKD. This research will have a significant impact on the field by 1) providing an understanding of mechanisms that contribute to the long term increased risk of cardiorenal disease following preeclamptic pregnancy and 2) providing preclinical studies to inform decisions regarding the perinatal care for women at risk of developing preeclampsia. Therefore, this work has important clinical and translational value as these findings could ultimately help us identify novel therapeutic targets to improve outcomes for women with a history of preeclampsia and identify treatment regimens to attenuate the long term risk of cardiovascular death in these women.

先兆子痫是当今世界孕产妇发病和死亡的主要原因之一， 影响了美国大约5%的怀孕。先兆子痫的特点是 由于妊娠后半期的高血压和蛋白尿的进行性发展， 沿着全身性内皮功能障碍。母亲的风险并不随着分娩而结束。 胎儿胎盘单位。经历先兆子痫的女性有更高的风险， 高血压、中风、心脏病和肾脏疾病，但导致这些疾病的机制 先兆子痫后的心血管和肾脏疾病尚不清楚。因此，有一个至关重要的 需要确定先兆子痫后妇女的最佳治疗方案。 不幸的是，缺乏自发的先兆子痫动物模型一直是一个障碍， 在治疗过程中和治疗后， 先兆子痫我们令人兴奋的初步数据表明，达尔盐敏感（达尔S）大鼠 在怀孕期间自发地发展先兆子痫的特征，其类似于 人类疾病，并加速心肾疾病和免疫激活，持续存在 产后这个模型将使我们能够通过检查 子痫前期妊娠对内皮功能、肾功能进展的长期影响 疾病和免疫激活的女性与预先存在的高血压，并确定是否 加强围产期血压管理将改善长期心血管健康 结果。这个项目将测试中心假设，先兆子痫的结果在一个持久的 产后免疫激活，使母亲易患内皮 功能障碍和CKD。这项研究将通过以下方式对该领域产生重大影响：1）提供 了解导致心肾疾病风险长期增加的机制 先兆子痫妊娠后的疾病和2）提供临床前研究，为决策提供信息 关于有患先兆子痫风险的妇女的围产期护理。因此，这项工作 具有重要的临床和转化价值，因为这些发现最终可以帮助我们识别 一种新的治疗靶点，以改善有先兆子痫病史的女性的结局， 确定治疗方案，以降低这些患者心血管死亡的长期风险， 妇女