DEXAMETHASONE STUDY

地塞米松研究

• 批准号: 7622779
• 负责人: CHARLES RICHARD NEAL
• 金额: $ 20.15万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622779
• 关键词: Adolescent Development; Adrenal Glands; Adult; Animal Model; Animals; Behavior; Behavior assessment; Behavioral; Brain; Centers of Research Excellence; Child; Clinical; Clinical Research; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Condition; Corticosterone; Corticotropin; Databases; Development; Dexamethasone; Environment; Extremely Low Birth Weight Infant; Funding; Glucocorticoids; Grant; Hawaii; Hippocampal Formation; Hospitals; Hypothalamic structure; In Situ Hybridization; Incidence; Infant; Institution; Link; Long-Term Effects; Low Birth Weight Infant; Measures; Medical; Mental Health; Molecular Genetics; Neonatal; Neonatal Intensive Care Units; Neonatology; Neuroanatomy; Neurologic; Neurosciences; Newborn Infant; Organism; Outcome; Pattern; Pituitary Gland; Pregnancy; Prematurity of fetus; Problem behavior; Radioimmunoassay; Rattus; Recording of previous events; Research; Research Design; Research Personnel; Resources; School-Age Population; Serum; Social isolation; Source; Stress; Survivors; Tissue Stains; Training; United States National Institutes of Health; Universities; Week; Woman; base; biological adaptation to stress; design; early experience; hypothalamic-pituitary-adrenal axis; mRNA Expression; neurogenesis; neuroimaging; postnatal; programs; pup; response; sound; tool

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 organisms 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 Kapiolani Women and Childrens 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 Hawaii 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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外源性糖皮质激素的长期过程。鉴于这些婴儿的极端早产，这种暴露发生在大脑成熟的时期，此时应激反应的边缘-下丘脑-垂体-肾上腺（LHPA）轴在高度应激的环境中正在经历显著的发育。越来越多的证据支持这样一种观点，即在正常情况下，LHPA应力轴将发展出一种对环境的反应模式，这种模式在很大程度上基于生物体早期的经验。该提案试图研究地塞米松暴露在新生儿期的长期影响，特别是在以后的发展过程中对压力的脆弱性。利用新生儿糖皮质激素治疗的动物模型，大鼠幼崽将被给予地塞米松，然后在青春期发育期间进行社会隔离。将在成人中测量LHPA轴的活动和行为应激反应（具体目标1）。随后将分析这些动物中应激轴内mRNA表达的变化以及海马结构中的神经发生和形态测定分析（具体目的2）。为了提供临床相关性，我们将建立一个来自卡皮新生儿重症监护室的低出生体重幸存者数据库olani妇女和儿童s医院。使用该数据库，我们将确定1989年至1999年期间出生的妊娠24至32周的婴儿暴露于出生后糖皮质激素（具体目标3）。利用该补助金第一年临床研究计划硕士的培训，将设计一项临床研究，使用行为评估和神经影像学来测量极端早产的DEX暴露学龄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）Nissl染色组织的大体形态学分析，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的联系，候选人希望更好地了解在有极端早产史的儿童中发现的行为问题高发率的机制。夏威夷大学临床卓越研究中心我会担任赞助机构。这个项目将导致一个健全的研究基础，和科学的独立性，作为候选人整合行为，发育神经解剖学和分子遗传学。这些工具将用于研究早期经验对后来的行为和认知发展的影响，将临床神经病学，发育神经解剖学和神经科学与儿童心理健康的改善联系起来。