PERINATAL HYPOXIA: ADRENOCORTICAL-METABOLIC ADAPTATIONS

描述（由申请人提供）：围产期和婴儿早期缺氧是死亡率和发病率的重要原因。肾上腺皮质激素是适应低氧应激的重要组成部分。此外，新生儿低氧性高脂血症是一个重要的临床实体，特定脂质代谢产物的变化会改变肾上腺功能。本建议的长期目标是表征围产期缺氧对大鼠下丘脑-垂体-肾上腺（HPA）系统和脂质代谢控制的短期和长期后果。具体目的1和2将评估新生儿缺氧对下丘脑-垂体-肾上腺轴控制的影响，通过评估类固醇生成的细胞内和全身控制，应激-低反应期（SHRP）的时间和机制，以及CRH和POMC表达和ACTH释放的负反馈控制。特异性目的3将通过评估成年大鼠随后的HPA对刺激的反应来表征围产期缺氧的长期后遗症。特异性Aim 4将通过分析新生儿缺氧与糖皮质激素治疗的相互作用，以及进行代谢组学分析，更全面地表征新生儿缺氧高脂血症。从出生开始的新生儿缺氧是通过将新生大鼠（及其泌乳坝）暴露在缺氧环境中来完成的。围产期缺氧是通过将妊娠晚期的怀孕大鼠暴露在缺氧环境中并让它们在缺氧环境中分娩来实现的。肾上腺皮质功能的生理、生化和分子评估是通过体内注射ACTH，使用分散细胞，评估StAR和PBR表达，测量CBG和糖皮质激素清除率。通过测量应激和crh诱导的ACTH释放、评估反馈敏感性、分析垂体、下丘脑和海马功能和相关受体/激素表达来评估下丘脑-垂体功能。代谢功能是通过分析肝酶活性，以及血清和肝脂的完整代谢组学分析来评估的。下丘脑-垂体-肾上腺和代谢对围产期缺氧的适应特征可以导致新的诊断方法和治疗，以减少发病率和死亡率。

DESCRIPTION (provided by applicant): Hypoxia during the perinatal period and during early infancy is a significant cause of mortality and morbidity. Adrenocortical hormones are a vital component of the adaptation to hypoxic stress. Furthermore, neonatal hypoxic hyperlipidemia is a significant clinical entity, and changes in specific lipid metabolites alter adrenal function. The long-term objective of this proposal is to characterize the short and long-term consequences of perinatal hypoxia on the control of the hypothalamic-pituitary-adrenal (HPA) system and lipid metabolism in the rat. Specific Aims 1 and 2 will evaluate the effect of neonatal hypoxia on the control of the hypothalamic-pituitary-adrenal axis by evaluating intracellular and systemic controllers of steroidogenesis, the timing and mechanisms of the stress-hyporesponsive period (SHRP), and the negative feedback control of CRH and POMC expression and ACTH release. Specific Aim 3 will characterize the long-term sequellae of perinatal hypoxia by evaluating subsequent HPA responses to stimuli in the adult rat. Specific Aim 4 will more fully characterize neonatal hypoxic hyperlipidemia by analyzing the interaction of neonatal hypoxia and glucocorticoid therapy, and by performing metabolomic analysis. Neonatal hypoxia from birth is accomplished by exposing newborn rats (with their lactating dams) to a hypoxic environment. Perinatal hypoxia is accomplished by exposing late-gestational pregnant rats to hypoxia and allowing them to deliver in a hypoxic environment. Physiological, biochemical and molecular assessment of adrenocortical function is performed by ACTH injection in vivo, using dispersed cells, evaluating StAR and PBR expression, and measuring CBG and glucocorticoid clearance. Hypothalamic-pituitary function is assessed by measuring stress- and CRH-induced ACTH release, by evaluating feedback sensitivity, and by analyzing pituitary, hypothalamic, and hippocampal function and pertinent receptor/hormone expression. Metabolic function is assessed by analysis of hepatic enzyme activity, as well as complete metabolomic analysis of serum and hepatic lipids. Characterization of the hypothalamic-pituitary-adrenal and metabolic adaptations to perinatal hypoxia can lead to new diagnostic approaches and therapies to minimize morbidity and mortality.