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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.

项目摘要/摘要