Prenatal Events-Postnatal Consequences

描述（由申请人提供）：过去30年来，产前护理的一项重大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，我们研究了在广泛使用的绵羊模型和青少年队列中产前类固醇治疗的编程效果。我们在绵羊中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）改变，包括血管紧张素转换酶2（ACE 2）降低，血管紧张素1型受体表达增加，以及增加的Ang II与Ang（1-7）的比率，所有这些都有利于与改变的RAS结合的Ang II刺激其1型受体而增加的张力，我们发现在动物模型中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）降低以及胰岛素抗性增加。在类固醇暴露的青少年中，存在较低的尿ACE 2、增加的尿Ang II与Ang（1-7）的比率和较高水平的尿白蛋白。因此，在动物模型和青少年中，对产前类固醇的反应似乎有几个共性。为了进一步确定这些编程效应及其后果，我们提出了一系列的研究，在这个应用程序中，以检查类固醇诱导的肾功能改变的机制（项目1和4），BRS（项目3和4），胰岛素抵抗（项目2和4）以及肥胖作为“第二次打击”的可能性并加剧了动物模型和青少年中产前类固醇暴露的影响（项目1，2和4）。我们的假设是，在肥胖的后代中，产前类固醇的不良编程效应将产生更大的影响。如果事实证明是这样，我们的研究将确定一个风险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，以减少高血压的风险，以及肾脏和代谢异常的产前类固醇暴露的个人。

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.