PERINATAL HYPOXIA: ADRENOCORTICAL-METABOLIC ADAPTATIONS

围产期缺氧：肾上腺皮质代谢适应

• 批准号: 6985329
• 负责人: HERSHEL RAFF
• 金额: $ 19.89万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985329
• 关键词: PERINATAL; HYPOXIA; ADRENOCORTICAL; METABOLIC; ADAPTATIONS

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.

描述(申请人提供)：围产期和早期婴儿期的缺氧是死亡和发病的一个重要原因。肾上腺皮质激素是适应低氧应激的重要组成部分。此外，新生儿缺氧性高脂血症是一种重要的临床实体，特定脂代谢产物的变化会改变肾上腺功能。这项建议的长期目标是描述围产期低氧对大鼠下丘脑-垂体-肾上腺(HPA)系统和脂代谢的控制的短期和长期后果。特异性AIMS 1和2将通过评估激素合成的细胞内和系统控制器、应激低反应期(SHRP)的时机和机制以及CRH和POMC表达和ACTH释放的负反馈控制来评估新生儿缺氧对下丘脑-垂体-肾上腺轴的控制作用。具体目标3将通过评估成年大鼠对刺激的后续HPA反应来表征围产期缺氧的长期后遗症。具体目标4通过分析新生儿缺氧与糖皮质激素治疗的相互作用，并进行代谢组学分析，将更全面地描述新生儿缺氧高脂血症的特征。新生儿从出生起就缺氧是通过将新生大鼠(及其哺乳母鼠)暴露在低氧环境中来实现的。围产期低氧是通过将妊娠晚期的大鼠暴露在低氧环境中并允许它们在低氧环境中分娩来实现的。通过体内注射ACTH，使用分散的细胞，评估STAR和PBR的表达，测量CBG和糖皮质激素清除，进行肾上腺皮质功能的生理、生化和分子评估。通过测量应激和CRH诱导的ACTH释放，通过评估反馈敏感性，以及通过分析垂体、下丘脑和海马体功能以及相关受体/激素的表达来评估下丘脑-垂体功能。代谢功能通过肝酶活性分析以及血清和肝脂的完整代谢组学分析来评估。表征下丘脑-垂体-肾上腺和代谢对围产期缺氧的适应性可以导致新的诊断方法和治疗方法，以最大限度地减少发病率和死亡率。

项目成果

Neonatal hypoxia in the rat: effects on exocrine pancreatic development.

大鼠新生儿缺氧：对外分泌胰腺发育的影响。

• DOI: 10.1097/00005176-200205000-00013
• 发表时间: 2002
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: Lee,PingC;Struve,Mark;Lewis,SuzanM;Raff,Hershel
• 通讯作者: Raff,Hershel

Growth hormone therapy during neonatal hypoxia in rats: body composition, bone mineral density, and insulin-like growth factor-1 expression.

大鼠新生儿缺氧期间的生长激素治疗：身体成分、骨矿物质密度和胰岛素样生长因子-1 表达。

• DOI: 10.1385/endo:16:2:139
• 发表时间: 2001
• 期刊: Endocrine
• 影响因子: 3.7
• 作者: Raff,H;Bruder,ED;Jankowski,B;Oaks,MK;Colman,RJ
• 通讯作者: Colman,RJ

Basal and adrenocorticotropin-stimulated corticosterone in the neonatal rat exposed to hypoxia from birth: modulation by chemical sympathectomy.

出生后暴露于缺氧的新生大鼠的基础和促肾上腺皮质激素刺激的皮质酮：化学交感神经切除术的调节。

• DOI: 10.1210/en.2003-1130
• 发表时间: 2004
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Raff,Hershel;Lee,JulieJ;Widmaier,EricP;Oaks,MartinK;Engeland,WilliamC
• 通讯作者: Engeland,WilliamC

Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR.

• DOI: 10.1152/ajpregu.00501.2002
• 发表时间: 2003
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: H. Raff;Julie J Hong;M. Oaks;E. Widmaier

Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth.

• DOI: 10.1152/physiolgenomics.00245.2006
• 发表时间: 2007-04
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: E. Bruder;J. J. Lee-J.;E. Widmaier;H. Raff