Preeclampsia and renal complications: late effects on kidney and vasculature

描述(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。它是发展中国家孕产妇死亡和发达国家早产的主要原因。PE的特点是妊娠20周后出现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的发病相关，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-sFlt1和可溶性endoglin-Seng)升高，而在女性PE临床症状和体征之前，促血管生成蛋白(胎盘生长因子-PlGF)水平降低。另一个得到快速积累的数据支持的观察结果是，在怀孕期间暴露在这种抗血管生成的环境中，会导致晚年心血管死亡率的显着增加。这种延迟“毒性”的机制尚不清楚。长期来看，在有PE病史的妇女中，有显著比例的肾功能受损，且呈“剂量-反应”相关关系：暴露于严重PE或反复PE中，在以后的生活中患ESRD的几率更高。有一些生物学证据表明，血管内皮细胞损伤和可能的表观遗传学变化是这些后遗症的起点。仔细分析相关的病理生理过程将有助于识别与疾病相关的可改变的危险因素，以及识别合适的治疗靶点，最终目标是减少后遗症。申请人打算(在啮齿动物上)进行活体研究，以调查先兆子痫在慢性肾功能衰竭等长期并发症的发病机制中的作用。这项工作不仅将促进对血管生成蛋白在PE中作用的了解，而且将为开发药物治疗提供必要的知识，以期在以后的生命中减少不同器官微血管中sFlt1和Seng的毒性。全身血管健康，特别是肾小球内皮“健康”，将在PE模型的设置中单独或与各种已知的心血管危险因素一起进行评估。将努力通过分析炎症和内皮功能图谱来确定潜在的机制。将进行药理学干预，旨在阐明相关的生物学途径，最终可能导致确定 治疗靶点。拟议的工作将在贝丝以色列女执事医学中心和哈佛医学院杰出的学术和研究环境下，在体育生物学专家S·阿南特·卡鲁曼奇博士的实验室进行。申请人是一名即将毕业的肾病学研究员，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者提供一个独特的机会来实现这个项目的目标，并开始作为一名独立调查人员的职业生涯。

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.