Preeclampsia and renal complications: late effects on kidney and vasculature

先兆子痫和肾脏并发症：对肾脏和脉管系统的后期影响

• 批准号: 9099837
• 负责人: Eliyahu Khankin
• 金额: $ 15.05万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099837
• 关键词: Affect; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animal Model; Animals; Aorta; Asses; Basic Science; Biological; Biology; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cerebral Edema; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Research; Data; Defect; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Dissection; Dose; Eclampsia; End stage renal failure; Endoglin; Environment; Epidemiologic Studies; Epigenetic Process; Exposure to; Fetal Growth Retardation; Fetus; Functional disorder; Future; Goals; Growth; Health; Human; Hypertension; Inflammation; Inflammatory; Injury; Interleukin-6; Intervention; Israel; Kidney; Kidney Diseases; Knowledge; Laboratories; Late Effects; Lead; Life; Link; Medical center; Mentors; Metabolic; Modeling; Modification; Morbidity - disease rate; Mus; NOS3 gene; Nature; Nephrology; Nephrons; Nitric Oxide; Nulliparity; Obesity; Organ; PGF gene; Pathogenesis; Pathway interactions; Pharmacotherapy; Phenotype; Pilot Projects; Placental Growth Factor; Play; Postpartum Period; Pre-Eclampsia; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Prevention; Prevention strategy; Preventive therapy; Process; Prostaglandins; Proteins; Proteinuria; Recommendation; Recording of previous events; Recovery; Recurrence; Renal function; Research; Research Personnel; Resistance; Risk; Risk Factors; Rodent; Rodent Model; Role; Second Pregnancy Trimester; Siblings; Signal Transduction; Signs and Symptoms; Sodium Chloride; TNF gene; Testing; Thrombophilia; Toxic effect; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Woman; Women' s Group; Work; base; cardiovascular disorder risk; cardiovascular risk factor; career; circulating biomarkers; cytokine; disease phenotype; endothelial dysfunction; improved; in vivo; inhibitor/antagonist; intercellular cell adhesion molecule; kidney vascular structure; medical complication; medical schools; modifiable risk; mortality; novel; novel therapeutic intervention; overexpression; pregnant; prevent; response; screening; therapeutic target; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Preeclampsia (PE) is the most common medical complication of pregnancy and affects 5-10% of pregnant women. It is the leading cause of maternal death in developing countries and premature delivery in developed nations. PE is characterized by new onset hypertension and proteinuria occurring after 20 weeks of gestation. Currently, the only treatment for PE is delivery. Recent research has shown that circulating anti-angiogenic proteins are associated with and may be involved in the pathogenesis of PE. In humans, antiangiogenic proteins (soluble fms-like tyrosine kinase-sFlt1 and soluble endoglin-sEng) are elevated, while levels of pro- angiogenic proteins (Placental Growth Factor-PlGF) are reduced in women prior to the clinical signs and symptoms of PE. Another observation which is supported by rapidly accumulating data is that exposure to this anti-angiogenic milieu during the pregnancy results in significant increase in cardiovascular mortality later in life. Mechanisms of this delayed "toxicity" are not clear. Long-term, renal function was shown to be impaired in significant proportion of women with past history of PE with "dose-response" like correlation observed: exposure to severe PE or recurrent PE, higher the chance of ESRD later in life. Some biologic evidence exists, that endothelial injury and possibly epigenetic changes in the vasculature is the starting point of those sequelae. Careful dissection of the pathophysiologic processes involved will help in identification of modifiable risk factors associated with the condition as well as recognition of suitable therapeutic targets with ultimate goal to reduce the sequelae. The applicant intends to do in vivo (on rodents) studies to investigate the prior preeclampsia in the pathogenesis of long term complications such as chronic renal failure. This work will not only advance the understanding of the role of angiogenic proteins in PE, but will also provide the necessary knowledge for development of drug therapies aimed at reducing sFlt1 and sEng toxicity in microvasculature of different organs later in life. Systemic vascular health and in particular glomerular endothelial "health" will be evaluated in setting of PE model alone or in addition to various know cardiovascular risk factors. Effort to identify potential mechanism will be made by means of analysis of inflammatory and endothelial function profiling in the proposed experimental groups. Pharmacologic interventions will be made aimed at elucidating relevant biological pathways involved, which ultimately could lead to identification of therapeutic targets. The proposed work will be performed in the laboratory of Dr. S. Ananth Karumanchi, an expert in PE biology, in the outstanding academic and research environment of Beth Israel Deaconess Medical Center and Harvard Medical School. The applicant is a Graduating Nephrology Fellow with rapidly developing and productive basic research background committed to research, understanding preeclampsia and reducing its impact on long term cardiovascular and renal morbidity and mortality. The combined expertise of mentors and collaborators will provide a unique opportunity for the applicant to achieve the goals of this project and to start a career as an independent investigator.

描述（由申请人提供）：先兆子痫（PE）是妊娠最常见的医学并发症，影响5-10%的孕妇。它是发展中国家产妇死亡和发达国家早产的主要原因。PE的特征是妊娠20周后新发高血压和蛋白尿。目前，PE的唯一治疗方法是分娩。最近的研究表明，循环中的抗血管生成蛋白与PE的发病有关，并可能参与PE的发病。在人类中，抗血管生成蛋白（可溶性fms样酪氨酸激酶-sFlt 1和可溶性内皮素-sEng）升高，而促血管生成蛋白（胎盘生长因子-PlGF）的水平在PE的临床体征和症状之前在女性中降低。另一个得到快速积累的数据支持的观察结果是，妊娠期间暴露于这种抗血管生成环境导致日后心血管死亡率显著增加。这种迟发性“毒性”的机制尚不清楚。在有PE既往史的女性中，长期肾功能受损的比例很大，观察到“剂量-反应”样相关性：暴露于重度PE或复发性PE，在以后的生活中发生ESRD的机会更高。存在一些生物学证据，即血管系统中的内皮损伤和可能的表观遗传变化是这些后遗症的起点。仔细解剖所涉及的病理生理过程将有助于识别与病情相关的可改变的风险因素，以及识别合适的治疗靶点，最终目标是减少后遗症。申请方拟进行体内（啮齿动物）研究，以研究既往先兆子痫在慢性肾衰竭等长期并发症发病机制中的作用。这项工作不仅将促进对血管生成蛋白在PE中的作用的理解，而且还将为开发旨在减少sFlt 1和sEng在生命后期不同器官微血管中的毒性的药物疗法提供必要的知识。将在单独的PE模型中或除各种已知的心血管风险因素外，评价全身血管健康，特别是肾小球内皮“健康”。将通过分析拟定实验组中的炎症和内皮功能谱来努力确定潜在机制。将进行药理学干预，旨在阐明相关的生物学途径，最终可能导致识别 治疗目标拟议的工作将在S博士的实验室进行。Ananth Karumanchi，PE生物学专家，在贝斯以色列女执事医疗中心和哈佛医学院杰出的学术和研究环境中。申请人是一名即将毕业的肾病研究员，具有快速发展和富有成效的基础研究背景，致力于研究，了解先兆子痫并减少其对长期心血管和肾脏发病率和死亡率的影响。导师和合作者的综合专业知识将为申请人提供一个独特的机会，以实现本项目的目标，并开始作为一个独立的调查员的职业生涯。