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

项目摘要/摘要 出生后发育迟缓在极低出生体重儿中仍然是一个重要的发病率，尽管具有攻击性和 现代肠外和肠内营养实践。已经确定了令人信服的关联-- 医院发育不全以及心脏代谢和神经发育障碍，加剧了进一步 确定早产儿的最佳营养需求。在动物和人类身上进行的研究表明， 钠(Na)的供应或摄取会损害身体的生长。极低出生体重儿(I)患钠的风险增加 由于尿钠大量流失(通常是未被意识到的)所致的衰竭，(Ii)缺乏渗透不活跃的钠池， 通常在妊娠晚期积聚，并可能在出生后动员起来，以维持循环中的钠池 (Iii)当供应高于通常所提供的量的钠时，表现出改善的躯体生长 临床实践。我们的目标是利用新的动物模型和实验室方法来解决 严重缺乏对生命早期钠稳态和代谢控制之间的联系的了解。私人投资促进局 产生了大量已发表的和初步的数据来支持他们的假设，即体内钠含量不足 早期生命通过激活AT1AR/GαI导致短期和长期能量消耗的程序性变化 在选定的下丘脑神经元中发出信号。我们将使用几种新的小鼠模型来解决这一假设 以(I)确定渗透失活钠池和脑RAS在代谢功能障碍中的作用 在生命早期由钠耗竭编程(目标1)，以及(Ii)探索AT1AR信号在Agti相关基因中的作用 下丘脑弓状核肽(AgRP)神经元介导能量消耗增加 生命早期钠耗竭小鼠随后的生长受限(目标2)。我们收集了一份研究报告 在尖端代谢表型、分子生物学和转基因方面拥有丰富经验的团队 动物生产是唯一准备解决这一临床相关问题的机构。这些研究的发现 将大大增加我们对早期生命钠动态平衡的作用和重要性的机械性理解。 生长、新陈代谢和能量流动，并可能导致范式转变的临床实践，解决 为早产儿提供充足的膳食钠，以优化一系列长期结果。

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.