Prenatal Events-Postnatal Consequences

产前事件-产后后果

• 批准号: 8712515
• 负责人: JAMES C. ROSE
• 金额: $ 143.36万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712515
• 关键词: 14 year old; Adolescent; Adrenal Cortex Hormones; Adult; Albumins; Angiotensin II; Angiotensins; Animal Experiments; Animal Model; Animals; Autacoids; Baroreflex; Betamethasone; Birth; Blood Pressure; Brain; Caring; Child; Chronic; Clinical; Clinical Research; Data; Development; Disease; Dose; Early Intervention; Epidemiologic Studies; Ethics; Event; Exposure to; Female; Fetal Lung; Funding; Glucocorticoids; Goals; Health; Human; Hypertension; Impairment; Incidence; Individual; Institution; Insulin Resistance; Intervention; Kidney; Kidney Diseases; Life Style; Light; Low Birth Weight Infant; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Neonatal; Neonatology; Nephrons; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peptidyl-Dipeptidase A; Perinatal Exposure; Physiological; Physiology; Population; Populations at Risk; Pregnancy; Pregnant Women; Premature Birth; Prenatal Nutrition; Prenatal care; Progress Reports; Relative (related person); Renal function; Renin; Renin-Angiotensin System; Research Personnel; Risk; Risk Factors; Series; Sheep; Sodium; Steroid therapy; Steroids; Stimulus; Structure; System; Time; Tissue Sample; Variant; Very Low Birth Weight Infant; Work; base; clinically relevant; cohort; fetal programming; heart rate variability; lung maturation; male; modifiable risk; offspring; postnatal; pregnant; premature; prenatal; prenatal exposure; pressure; programs; receptor; receptor expression; response; trait; urinary; young adult

DESCRIPTION (provided by applicant): A significant development in prenatal care over the last 30 years is the treatment of pregnant women at risk for premature delivery with synthetic corticosteroids to facilitate fetal lung maturation. However, data from experimental animals and epidemiological studies have raised concerns about the possible untoward consequences of prenatal exposure to excess glucocorticoids. During the past five years we have studied the programming effects of antenatal steroid therapy in a widely used sheep model and in a cohort of adolescents. Among the programming effects of antenatal steroids we have observed in the sheep are increases in blood pressure, reductions in nephron number, alterations in the intrarenal renin-angiotensin system (RAS) including decreased angiotensin converting enzyme 2 (ACE2), increased angiotensin type 1 receptor expression, and an increased Ang li to Ang(1-7) ratio all of which favor increased tone from Ang li stimulation of its type 1 receptor in conjunction with the altered RAS, we find impairments in the ability to excrete a sodium load, decreases in baroreflex sensitivity (SRS) and heart rate variability (HRV) and increases in insulin resistance in the animal model. In the steroid exposed adolescents there is lower urinary ACE2, an increased ratio of urinary Ang il to Ang (1-7) and higher levels of urinary albumin. Thus, there appear to be several commonalities in the responses to antenatal steroids in the animal model and the adolescents. To further establish these programming effects and their consequences, we propose a series of studies in this application to examine the mechanisms of the steroid-induced alterations in renal function (Projects 1 & 4), BRS (Projects 3 & 4), insulin resistance (Projects 2 & 4) and the possibility that obesity acts as a "second hit" and exacerbates the effects of antenatal steroid exposure in both the animal model and the adolescents (Projects 1, 2 & 4). Our hypothesis is that there will be greater impact of the adverse programming effects of antenatal steroids in offspring who are obese. If this proves to be the case our studies will identify an at risk population and a modifiable risk factor. Therefore our work may promote the identification of new, early intervention strategies to reduce the risk of hypertension as well as renal and metabolic abnormalities in antenatal steroid exposed individuals.

描述（由申请人提供）：在过去的30年里，产前护理的一个重要发展是用合成皮质类固醇治疗有早产风险的孕妇，以促进胎儿肺成熟。然而，来自实验动物和流行病学研究的数据引起了人们对产前暴露于过量糖皮质激素可能产生的不良后果的担忧。在过去的五年中，我们在广泛使用的绵羊模型和青少年队列中研究了产前类固醇治疗的编程效应。我们在绵羊身上观察到的产前类固醇的编程效应包括血压升高、肾单位数量减少、肾内肾素-血管紧张素系统（RAS）的改变，包括血管紧张素转换酶2 （ACE2）的降低、血管紧张素1型受体表达的增加以及Ang li / Ang（1-7）比值的增加，所有这些都有利于Ang li刺激其1型受体并改变RAS的音调。在动物模型中，我们发现排泄钠负荷的能力受损，压力反射敏感性（SRS）和心率变异性（HRV）降低，胰岛素抵抗增加。在类固醇暴露的青少年中，尿ACE2较低，尿il与Ang的比值增加（1-7），尿白蛋白水平较高。因此，动物模型和青少年对产前类固醇的反应似乎有几个共同点。为了进一步确定这些编程效应及其后果，我们在本应用程序中提出了一系列研究，以检查类固醇诱导的肾功能改变（项目1和4）、BRS（项目3和4）、胰岛素抵抗（项目2和4）的机制，以及肥胖作为“二次打击”的可能性，并加剧了动物模型和青少年产前类固醇暴露的影响（项目1、2和4）。我们的假设是，对于肥胖的后代，产前类固醇的不良编程效应会产生更大的影响。如果事实证明是这样，我们的研究将确定一个高危人群和一个可改变的风险因素。因此，我们的工作可能会促进识别新的早期干预策略，以降低产前类固醇暴露个体患高血压以及肾脏和代谢异常的风险。