Neonatal Growth and the Neurodevelopmental Origins of Hypertension

新生儿生长和高血压的神经发育起源

基本信息

批准号：
8274730
负责人：
ROBERT D ROGHAIR
金额：
$ 37.13万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274730
关键词：
Adult Angiotensin II Angiotensin II Receptor Angiotensin II Type 1 Receptor Blockers Angiotensins Anorexia Birth Weight Blood Pressure Breeding C57BL/6 Mouse Cardiovascular Diseases Cardiovascular system Commit Data Development Disease susceptibility Environmental Risk Factor Fetal Growth Retardation Growth Growth and Development function Health Hormonal Human Human Characteristics Hypertension Hypothalamic structure Infant formula Infusion procedures Intervention Lactation Leptin Leptin deficiency Leptin resistance Life Link Losartan Malnutrition Measurement Metabolic Modeling Molecular Mus Neonatal Obesity Obesity Related Hypertension Pathway interactions Perinatal Phenotype Plasma Play Population Premature Birth Premature Infant Prevention program Production Program Development Psychological Stress Public Health Rattus Receptor Signaling Regulation Renin-Angiotensin System Replacement Therapy Resistance Rest Risk Risk Factors Role Serum Signal Transduction Starvation Stress Superoxides Supplementation Testing Third Pregnancy Trimester Time Translating Weight World Health Organization base cardiovascular risk factor high risk infant mouse model neonate neurodevelopment neuronal patterning neurotrophic factor novel offspring paraventricular nucleus premature programs psychologic public health relevance pup response restraint stress

项目摘要

DESCRIPTION (provided by applicant): Perinatal growth restriction is an independent risk factor for the development of hypertension. Once the environmental risk factors that contribute to cardiovascular risk are understood, underlying mechanisms can be identified and preventative strategies can be developed. In rat models, maternal undernutrition during lactation induces neonatal growth restriction, neonatal leptin deficiency, altered hypothalamic development, and obesity- related resistance to leptin-induced anorexia. While obesity is associated with resistance to the metabolic effects of leptin, emerging evidence suggest preserved leptin-dependent sympathetic signaling contributes to obesity-related hypertension. To explore the role of leptin in the neurodevelopmental origins of hypertension, we developed a novel non-interventional model in isogenic mice. Within our large breeding colony, we identified mice of average birth weight but with a weanling weight below the 10th percentile. Neonatal growth restriction led to profound neonatal leptin deficiency, reduced adult hypothalamic volumes, resting hypertension and increased sympathetic tone. Compared to control offspring, growth restricted mice had exaggerated pressor responses to central leptin administration and psychological stress. The stress-evoked hypertension was associated with hypothalamic activation and was abolished by central angiotensin II receptor blockade. We went on to show 1) central leptin administration elicits hypothalamic renin angiotensin system (RAS) activation and 2) leptin supplementation during incipient neonatal growth restriction blocks the programming of adult hypertension. Based on these data, we hypothesize that neonatal growth restriction-induced leptin deficiency programs adult hypertension through a persistent enhancement in central leptin and angiotensin II signaling. We will test the following hypotheses: I) Neonatal growth restriction enhances central leptin and angiotensin II signaling, particularly within the paraventricular nucleus of the hypothalamus; II) Neonatal leptin antagonist exposure induces adult hypertension in normally grown mice; and III) Neonatal leptin supplementation blocks the programming of adult hypertension by normalizing hypothalamic growth and central angiotensin II signaling. Our studies thus seek to identify: I) a novel interaction between leptin and the RAS in the regulation of arterial blood pressure, II) the molecular pathways that contribute to the expression of programmed hypertension; III) a neurotrophic factor deficiency that triggers adult hypertension, and IV) a hormonal replacement therapy that can be readily translated to the prevention of programmed hypertension. Our team is committed to understanding the effects of neonatal growth restriction on neurodevelopment, as we seek to develop novel interventions targeted to malleable windows of development that could transform our management of neonates at risk of developing life-long cardiovascular disease. PUBLIC HEALTH RELEVANCE: Neonatal growth restriction increases the risk of life-threatening cardiovascular disease. Once the underlying mechanisms are defined, preventative strategies can be developed. This proposal seeks to define strategies to optimize neonatal development and preserve cardiovascular health.

描述（由申请人提供）：围产期生长限制是高血压发展的独立风险因素。一旦了解了导致心血管风险的环境风险因素，就可以确定基本的机制并可以制定预防策略。在大鼠模型中，泌乳过程中的母体营养不良会诱导新生儿的生长限制，新生儿瘦素缺乏症，下丘脑发育改变以及对瘦素诱导的厌食症的肥胖相关性。尽管肥胖与瘦素代谢作用的抗性有关，但新兴的证据表明保留的瘦素依赖性交感神经信号传导有助于与肥胖相关的高血压。为了探索瘦素在高血压的神经发育起源中的作用，我们在等源性小鼠中开发了一种新型的非差异模型。在我们的大型繁殖群落中，我们确定了平均出生体重的小鼠，但断奶重量低于第10％。新生儿的生长限制导致新生儿瘦素缺乏症，成年下丘脑体积减少，静息高血压和同情性张力增加。与对照后代相比，受限制的小鼠对中央瘦素给药和心理压力的反应夸大了。应激诱发的高血压与下丘脑激活有关，并被中央血管紧张素II受体阻滞剂废除。我们继续显示1）中央瘦素给药会引起下丘脑肾素血管紧张素系统（RAS）激活和2）在初期新生儿生长限制期间补充瘦素，阻止了成人高血压的编程。基于这些数据，我们假设新生儿生长限制诱导的瘦素缺乏计划是通过持续增强中央瘦素和血管紧张素II信号传导的持续增强而成人高血压的。我们将检验以下假设：i）新生儿生长限制增强了中央瘦素和血管紧张素II信号传导，尤其是在下丘脑的副脑核内； ii）新生儿瘦素拮抗剂暴露会诱导正常生长的小鼠成人高血压； iii）新生儿瘦素补充剂通过使下丘脑生长和中央血管紧张素II信号传导来阻止成人高血压的编程。因此，我们的研究试图识别：i）在调节动脉血压的调节中，瘦素与RA之间的新型相互作用，ii）有助于编程高血压表达的分子途径； iii）一种神经营养因子缺乏症，可触发成人高血压，iv）一种激素替代疗法，可以很容易地转化为预防程序性高血压。我们的团队致力于了解新生儿生长限制对神经发育的影响，因为我们试图开发针对可延展的发展窗口的新颖干预措施，这些干预措施可能会改变我们对患有终身性心血管疾病风险的新生儿的管理。公共卫生相关性：新生儿的生长限制增加了威胁生命的心血管疾病的风险。一旦定义了基本机制，就可以制定预防策略。该建议旨在定义优化新生儿发展并保留心血管健康的策略。