Fetal Cardiomyocyte Fatty Acid Metabolism is impaired in Intrauterine Growth Restriction

宫内生长受限胎儿心肌细胞脂肪酸代谢受损

• 批准号: 10392389
• 负责人: Rachel Drake
• 金额: $ 5.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392389
• 关键词: Adult; Affect; Animals; BODIPY; Birth; CD36 gene; Cardiac Myocytes; Cardiovascular Diseases; Carnitine Palmitoyltransferase I; Cause of Death; Cell physiology; Cells; Cellular Membrane; Chronic Disease; Confocal Microscopy; Diabetes Mellitus; Environment; Esterification; Fatty Acids; Fetal Growth Retardation; Fetal Heart; Fetal Sheep; Fetus; Fluorescence; Future; Gene Expression; Gene Proteins; Genes; Genus Hippocampus; Glucose; Goals; Growth; Heart; Heart failure; Human; Hypoglycemia; Hypoxemia; Impairment; Label; Laboratory Study; Life; Lipids; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Myocardial; Myocardial dysfunction; Myocardium; Nutrient; Nutritional; Obesity; Oxides; Oxygen; Oxygen Consumption; Palmitates; Pathway interactions; Physiological; Physiology; Placental Insufficiency; Pregnancy; Premature Infant; Preparation; Process; Production; Risk; Series; Serum; Sheep; Stress Tests; Techniques; Therapeutic Embolization; Thin Layer Chromatography; United States; acylcarnitine; body system; cardiogenesis; cardiovascular health; clinically relevant; experimental study; fatty acid metabolism; fatty acid oxidation; fatty acid transport; fetal; glucose tolerance; heart function; improved; in utero; in vivo; insight; intrauterine environment; lipidomics; live cell imaging; long chain fatty acid; nutrition; oxidation; postnatal; prenatal stress; prevent; protein expression; response; sheep model; therapy development; uptake

Project Summary Babies who have suffered from placental insufficiency resulting in intrauterine growth restriction (IUGR) are more vulnerable for metabolic and cardiovascular disease postnatally. However, the mechanisms underlying this increased risk are poorly understood. Adaptations made by the fetus in response to placental insufficiency changes the trajectory for cellular function with lifelong consequences. Fetal organs and systems must develop and prepare for an extrauterine environment which involves an abrupt change in oxygen and nutritional substrates. The fetal heart utilizes primarily glucose and lactate as fuel and transitions to primarily fatty acid metabolism postnatally. This shift to fatty acid oxidation occurs concomitant with a doubling in oxygen levels at birth. The physiological preparation of the myocardium for this transition to fatty acid oxidation is poorly understood and the consequences of a suboptimal intrauterine environment on these processes is not known. Umbilicoplacental embolization is a well-established, clinically relevant model of placental insufficiency in sheep. This model leads to fetal hypoxemia, hypoglycemia and intrauterine growth restriction and has been used to investigate the effect of IUGR on several organ systems. With respect to the heart, growth and maturation is slowed, though little is known about the effects on metabolic pathways. Postnatally, IUGR sheep have altered glucose tolerance and sensitivity. This metabolic change is likely to have been initiated in utero as IUGR fetal sheep have impaired glucose oxidation. To the best of our knowledge, nothing is known about the effect of IUGR on fatty acid processing. However, IUGR sheep have a tendency to be more obese compared to control sheep, suggesting lipid handling may also be altered by placental insufficiency. Alterations to lipid handling in utero could have lifelong consequences on cardiac function due to alterations in energy production. The goal of this project is to determine whether fatty acid metabolism is impacted by placental insufficiency using the umbilicoplacental embolization model in sheep. The mechanisms involved in fatty acid uptake and metabolism will be systematically examined using an array of techniques including live cell imaging, lipidomics, mitochondrial stress tests and gene and protein expression analysis. This study will determine how this prenatal stress alters cardiomyocyte metabolism and may guide future therapies for improving nutrition practices and/or cardiovascular health.

项目摘要 因胎盘功能不全而导致胎儿宫内生长受限的婴儿 出生后更容易患代谢和心血管疾病。然而，潜在的机制 人们对这种增加的风险知之甚少。胎儿对胎盘功能不全的适应 改变细胞功能的轨迹，带来终生后果。胎儿器官和系统必须发育 并为宫外环境做好准备，这涉及到氧气和营养的突然变化 底物。胎儿心脏主要利用葡萄糖和乳酸作为燃料，并转变为主要脂肪酸。 生后新陈代谢。这种向脂肪酸氧化的转变伴随着氧气水平的翻倍 出生。对于这种向脂肪酸氧化的转变，心肌的生理准备很差。 了解，次佳的宫内环境对这些过程的后果尚不清楚。 脐带胎盘栓塞术是一种成熟的、临床相关的胎盘功能不全模型。 羊。这种模型会导致胎儿低氧血症、低血糖和宫内生长受限，并已被 用于研究宫内发育迟缓对几个器官系统的影响。关于心灵，成长和 成熟是缓慢的，尽管对代谢途径的影响知之甚少。出生后，IUGR绵羊 改变了葡萄糖耐量和敏感度。这种代谢变化很可能是在子宫内启动的，因为 IUGR胎羊对葡萄糖氧化有一定的损伤作用。据我们所知，关于 IUGR对脂肪酸加工的影响然而，与IUGR绵羊相比，IUGR绵羊有更肥胖的趋势 来控制绵羊，这表明胎盘功能不全也可能改变脂质的处理。血脂的变化 由于能量产生的变化，在子宫中处理可能会对心脏功能产生终身影响。 该项目的目标是确定胎盘功能不全是否会影响脂肪酸代谢。 采用羊脐带胎盘栓塞术模型。参与脂肪酸摄取的机制和 代谢将使用一系列技术进行系统研究，包括活细胞成像、脂质组学、 线粒体应激测试和基因和蛋白质表达分析。这项研究将确定这一点 产前应激改变心肌细胞代谢，并可能指导未来改善营养的治疗 实践和/或心血管健康。