Impact of Early Life Sodium Intake on Growth and Metabolism – Role of Hypothalamic Mechanisms

生命早期钠摄入量对生长和代谢的影响 — 下丘脑机制的作用

基本信息

批准号：
10493724
负责人：
Justin L Grobe
金额：
$ 48.7万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-12 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10493724
关键词：
Address Adipose tissue Adult Age-Months Angiotensin Type 1a Receptor Angiotensins Animal Model Animals Area Basal metabolic rate Birth Brain Cardiometabolic Disease Cells Clinical Clozapine Coupled Couples Data Dependence Development Disinhibition Energy Metabolism Engineering Enteral Nutrition Equilibrium Failure Fatty acid glycerol esters Growth Health Homeostasis Hospitals Human Hypothalamic structure Impairment Infant Intake Intervention Knowledge Laboratories Leptin Life Link Macronutrients Nutrition Mediating Metabolic Control Metabolic dysfunction Metabolism Methodology Micronutrients Modeling Modernization Molecular Biology Morbidity - disease rate Mus Muscarinic Acetylcholine Receptor Neurodevelopmental Disorder Neurodevelopmental Impairment Neurologic Neurons Neurotransmitters Nutritional Outcome Oxides Parenteral Nutrition Peptides Play Practice Guidelines Pregnancy Premature Infant Production Proteins Publishing Receptor Activation Receptor Gene Receptor Signaling Renin-Angiotensin System Research Research Design Risk Rodent Model Role Second Messenger Systems Serum Signal Transduction Sodium Stimulus Structure of nucleus infundibularis hypothalami Techniques Testing Tissues Transgenic Animals Transgenic Organisms Urine Very Low Birth Weight Infant Weight Gain cardiometabolism cell type clinical practice clinically relevant critical period dietary energy balance experience human model improved metabolic phenotype mouse model neuronal cell body neurotransmission novel novel strategies postnatal receptor response

项目摘要

Project Summary / Abstract Postnatal growth failure remains a significant morbidity in very low birth weight infants despite aggressive and modern parenteral and enteral nutrition practices. Compelling associations have been identified between in- hospital growth failure and cardiometabolic and neurodevelopmental disorders, heightening the need to further identify optimal nutritional needs of preterm infants. Studies in animals and humans demonstrate deficiencies in sodium (Na) supply or intake impair somatic growth. Very low birth weight infants (i) are at increased risk of Na depletion due to high (and often unappreciated) urine Na loss, (ii) lack osmotically-inactive Na pools that are normally accrued during late gestation and are likely mobilized after birth to maintain circulating Na pools, and (iii) demonstrate improved somatic growth when supplied with Na in amounts above that typically provided in clinical practice. Our objective is to utilize novel animal models and laboratory methodologies to address the critical lack of understanding of the links between Na homeostasis in early life and metabolic control. The PIs have generated a wealth of published and preliminary data supporting their hypothesis that insufficient Na in early life causes programmed changes in short-and long-term energy expenditure via activation of AT1AR/Gαi signaling in selected hypothalamic neurons. We will address this hypothesis using several new mouse models to (i) identify the role that osmotically-inactive Na pools and the brain RAS play in metabolic dysfunctions programmed by Na depletion in early life (Aim 1), and (ii) explore the role of AT1AR signaling within Agouti-related peptide (AgRP) neurons of the hypothalamic arcuate nucleus in mediating increased energy expenditure & subsequent growth restriction in mice with Na depletion in early life (Aim 2). We have assembled a research team with extensive experience with cutting-edge metabolic phenotyping, molecular biology and transgenic animal production that is uniquely poised to address this clinically relevant issue. Findings from these studies will greatly increase our mechanistic understanding of the role and importance of early-life Na homeostasis in growth, metabolism and energy flux and potentially result in paradigm-shifting clinical practices which address providing sufficient dietary Na to premature infants to optimize a spectrum of long-term outcomes.

项目概要/摘要尽管具有攻击性和攻击性，但出生后生长障碍仍然是极低出生体重婴儿的重要发病率。现代肠外和肠内营养实践之间已发现了令人信服的关联。医院生长衰竭以及心脏代谢和神经发育障碍，更加需要进一步确定早产儿的最佳营养需求对动物和人类的研究表明存在缺陷。钠 (Na) 的供应或摄入会损害身体生长。出生体重极低的婴儿 (i) 摄入钠的风险增加。由于高（且常常未被意识到）尿钠流失而导致的消耗，（ii）缺乏渗透压不活跃的钠池通常在妊娠晚期产生，并且可能在出生后被动员以维持循环的钠池，并且 (iii) 当提供的钠含量高于通常提供的钠含量时，证明体细胞生长得到改善我们的目标是利用新的动物模型和实验室方法来解决这个问题。对生命早期 Na 稳态与代谢控制之间的联系严重缺乏了解。产生了大量已发表的初步数据，支持他们的假设，即钠含量不足生命早期通过 AT1AR/Gαi 的激活导致短期和长期能量消耗的程序性变化我们将使用几种新的小鼠模型来解决这一假设。 (i) 确定渗透不活跃的钠池和大脑 RAS 在代谢功能障碍中的作用由早期生命中 Na 消耗所编程（目标 1），以及 (ii) 探索 AT1AR 信号在 Agouti 相关中的作用下丘脑弓状核的肽（AgRP）神经元介导能量消耗增加和生命早期钠缺乏的小鼠随后的生长受限（目标 2）。团队在尖端代谢表型、分子生物学和转基因方面拥有丰富的经验这些研究的结果特别适合解决这一临床相关问题。将大大增加我们对生命早期Na稳态的作用和重要性的机制理解生长、新陈代谢和能量通量，并可能导致范式转变的临床实践，解决为早产儿提供足够的膳食钠，以优化一系列长期结果。