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

项目总结/摘要 出生后生长障碍仍然是一个显着的发病率极低出生体重儿， 现代肠外和肠内营养实践。已经确定了在- 医院生长障碍和心脏代谢和神经发育障碍，增加了进一步 确定早产儿的最佳营养需求。对动物和人类的研究表明， 钠（Na）供应或摄入损害躯体生长。极低出生体重儿（i）患Na的风险增加 由于高（通常不受重视）尿钠损失而导致的消耗，（ii）缺乏 通常在妊娠晚期积累，出生后可能被动员以维持循环Na池， (iii)当以高于通常提供的量提供Na时，显示出改善的体细胞生长。 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与代谢控制之间联系的理解。法律与正义党 已经产生了丰富的已发表和初步的数据支持他们的假设， 生命早期通过激活AT 1AR/Gαi引起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的信号。我们将使用几种新的小鼠模型来解决这一假设 （i）确定无活性Na池和脑RAS在代谢功能障碍中的作用 （二）探讨AT 1AR信号转导在Agouti相关神经元中的作用。 肽（AgRP）神经元的下丘脑弓状核在介导增加的能量消耗和 随后在生命早期Na耗竭的小鼠中生长受限（目的2）。我们组织了一项研究 在代谢表型分析、分子生物学和转基因领域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。这些研究的结果 这将大大增加我们对生命早期Na稳态的作用和重要性的机械理解， 生长，代谢和能量通量，并可能导致范式转变的临床实践， 为早产儿提供充足的膳食钠，以优化长期结局。

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.