Prenatal Events-Postnatal Consequences

描述(由申请人提供)：本项目申请的主要目标是调查产前接触合成糖皮质激素对出生后肾功能和血压的长期影响。这一课题在今天具有重大意义，因为合成糖皮质激素在围产期的临床应用广泛，以促进肺成熟。拟议的研究包括在同一广泛使用的动物模型(处于不同发育阶段的绵羊)中的三个项目，以检查特定的系统和机制，这些系统和机制调节产前类固醇治疗对肾脏发育和功能、心血管系统的神经控制和血压的影响。他们与一个临床项目相结合，在10-16岁的儿童中记录糖皮质激素暴露对血压、血压响应性和肾功能指数的影响。具体地说，项目1研究了产前接触类固醇对肾脏内肾素-血管紧张素系统、体内肾功能和不同发育阶段血压的影响。项目2采用体外和活体两种方法，重点研究了产前类固醇暴露对肾脏处理钠的影响。项目3确定了产前糖皮质激素对脑肾素血管紧张素系统、压力感受器功能和交感神经流出调节的影响。最后，项目4在明确定义的患者群体中建立了产前类固醇暴露对血压的影响、血压对刺激的反应以及对儿童肾功能指数的影响，以及这种影响如何受到生长和健康等因素的调节。因此，所有动物项目都具有高度的科学整合性，临床项目的结果将为动物模型的工作提供高度的相关性。所获得的数据将提高我们对产前使用糖皮质激素的后果的理解，并可能有助于识别成年后有患高血压风险的儿童群体。这一结果显然会刺激制定监测和早期干预策略，以便在出生前接触糖皮质激素的儿童使用。因此，拟议研究的长期益处可能是减少与血压升高相关的总体发病率。

DESCRIPTION (provided by the applicant): The primary goal of this program project application is to investigate the long-term effects of antenatal exposure to synthetic glucocorticoids on renal functional and blood pressure postnatally. This topic has major significance today because of the widespread clinical use of synthetic glucocorticoids in the perinatal period to enhance lung maturation. The proposed studies encompass three projects in the same, widely used animal model (the sheep at different stages of development) to examine specific systems and mechanisms mediating the effects of antenatal steroid treatment on aspects of kidney development and function, the neural control of the cardiovascular system and blood pressure. They are coupled with a clinical project to document in children between 10-16 years of age, the effects of glucocorticoid exposure on blood pressure, blood pressure responsivity and indices of renal function. Specifically, Project 1 examines the impact of prenatal steroid exposure on the intra-renal renin-angiotensin system, renal function in vivo and blood pressure at different stages of development. Project 2 focuses on the effects of prenatal steroid exposure on sodium handling by the kidney using both in vitro and in vivo approaches. Project 3 establishes the impact of antenatal glucocorticoids on the brain renin angiotensin system, baroreceptor function and the regulation of sympathetic outflow. Finally, Project 4 establishes, in a well-defined patient population, the impact of prenatal steroid exposure on blood pressure, the responsiveness of blood pressure to stimulation and on indices of renal functional in children and how this impact is modulated by factors such as growth and fitness. Thus, all the animal projects have a high level of scientific integration and the results of the clinical project will provide a high level of relevance for the work in the animal model. The data obtained will improve our understanding of the consequences of the use of glucocorticoids antenatally and may help to identify a population of children at risk for the development of high blood pressure as adults. This outcome would obviously serve as a stimulus for the development of monitoring and early intervention strategies to be used in children exposed to glucocorticoids prior to birth. Thus, a long-term benefit of the proposed studies may be to reduce the overall morbidity associated with elevations in blood pressure in such a population.