DEXAMETHASONE STUDY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。作为药物治疗的结果，极低出生体重儿在新生儿早期经常暴露于较长的外源性糖皮质激素疗程。鉴于这些婴儿的极早产儿，这种暴露发生在大脑成熟期，此时对应激反应敏感的边缘-下丘脑-垂体-肾上腺(LHPA)轴在高度应激环境中经历显著发育。越来越多的证据支持这一观点，即在正常条件下，LHPA应激轴将在很大程度上发展出一种对环境的反应模式，这在很大程度上是基于有机体的早期经验。这项建议试图研究地塞米松在新生儿期暴露的长期影响，特别是关于在以后发育过程中对压力的易感性。利用新生糖皮质激素治疗的动物模型，大鼠幼崽将被注射地塞米松，然后在青春期发育期间受到社会隔离。将在成人中测量LHPA轴的活动和行为应激反应(特定目标1)。随后将分析这些动物应激轴内的mRNA表达的变化，以及海马结构中的神经发生和形态计量学分析(特定目标2)。为了提供临床相关性，我们将开发一个来自卡皮奥拉尼妇女儿童S医院新生儿重症监护病房的低出生体重幸存者的数据库。使用这个数据库，我们将确定1989年至1999年期间出生的在24至32周孕期之间出生的婴儿是否接触了出生后糖皮质激素(具体目标3)。在这笔赠款的第一年，利用临床研究硕士项目的培训，一项临床研究将设计使用行为评估和神经成像来衡量极早产学龄期幸存者的神经发育结果。使用的工具包括a)新生大鼠神经学检查，b)成年大鼠行为分析，c)大鼠血清皮质酮和ACTH RIA，d)原位杂交，e)尼氏染色组织大体形态分析，f)神经发生分析和g)临床研究设计。通过研究新生儿早期不良经历与成人行为改变之间的联系，候选人希望更好地理解极端早产史儿童行为问题高发的机制。夏威夷大学的临床卓越研究中心将是赞助机构。这个项目将导致坚实的研究基础和科学独立性，因为候选人整合了行为学、发育神经解剖学和分子遗传学。这些工具将通过将临床新生儿学、发育神经解剖学和神经科学与改善儿童心理健康联系起来，研究早期经验对以后行为和认知发展的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As a consequence of medical treatment, extremely low birth weight infants are often exposed to a prolonged course of exogenous glucocorticoids during the early neonatal period. Given the extreme prematurity of these infants, this exposure occurs during a period of brain maturation when the stress-responsive limbic-hypothalamic-pituitary-adrenal (LHPA) axis is undergoing significant development in a highly stressed environment. Mounting evidence supports the notion that under normal conditions the LHPA stress axis will develop a pattern of responses to the environment that are to a great extent, based on an organism¿s early experiences. This proposal attempts to study long-term effects of dexamethasone exposure in the neonatal period, particularly regarding vulnerability to stress during later development. Utilizing an animal model of neonatal glucocorticoid treatment, rat pups will be administered dexamethasone, then be subject to social isolation during adolescent development. Activity of the LHPA axis and behavioral stress responses will be measured in adults (specific aim 1). This will be followed by analysis of alterations in mRNA expression within the stress axis in these animals as well as neurogenesis and morphometric analyses in the hippocampal formation (specific aim 2). To provide clinical correlation, we will develop a database of low birth weight survivors from the neonatal intensive care unit at Kapi¿olani Women and Children¿s Hospital. Using this database we will identify infants born between 24 and 32 weeks gestation between 1989 and 1999 who were exposed to postnatal glucocorticoids (specific aim 3). Capitalizing on training from the Masters in Clinical Research Program during the first year of this grant, a clinical study will be designed to use behavioral assessments and neuroimaging to measure neurodevelopmental outcomes in DEX-exposed school-age survivors of extreme prematurity. Tools to be used include a) neonatal rat neurological exams, b) adult rat behavioral analyses, c) rat serum corticosterone and ACTH RIA, d) in situ hybridization, e) gross morphological analysis of Nissl-stained tissues, f) analyses of neurogenesis and g) clinical research design. By studying the linkage of adverse early experience in the newborn period with alteration of behavior in the adult, the candidate hopes to better understand mechanisms involved in the high incidence of behavioral problems identified in children with a history of extreme prematurity. The Clinical Center for Research Excellence at the University of Hawai¿i will be the sponsoring institution. This project will result in a sound research base, and scientific independence, as the candidate integrates behavior, developmental neuroanatomy and molecular genetics. These tools will be used to study effects of early experience on later behavior and cognitive development by linking clinical neonatology, developmental neuroanatomy and neurosciences with improvement of mental health in children.