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: 9761204
• 负责人: Rachel Drake
• 金额: $ 5万
• 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/9761204
• 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; 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; live cell imaging; long chain fatty acid; nutrition; oxidation; postnatal; prenatal stress; prevent; protein expression; response; 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 患有胎盘功能不全导致宫内生长受限（IUGR）的婴儿， 出生后更容易患上代谢和心血管疾病。然而，其背后的机制 这种增加的风险知之甚少。胎儿对胎盘功能不全的适应 改变了细胞功能的轨迹，并带来终身的后果。胎儿的器官和系统必须发育 并为子宫外环境做好准备，这涉及氧气和营养的突然变化， 印刷受体.胎儿心脏主要利用葡萄糖和乳酸盐作为燃料，并主要转化为脂肪酸 产后代谢这种向脂肪酸氧化的转变伴随着氧水平的加倍而发生， 出生心肌对于这种向脂肪酸氧化的转变的生理准备很差 然而，不理想的子宫内环境对这些过程的影响尚不清楚。 脐胎盘栓塞是一种成熟的、临床相关的胎盘功能不全模型， 羊该模型导致胎儿低氧血症、低血糖和宫内生长受限， 用于研究IUGR对几个器官系统的影响。关于心脏，生长和 成熟减慢，但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性。这种代谢变化很可能是在子宫内开始的， IUGR胎羊存在葡萄糖氧化受损。据我们所知，没有什么是已知的。 IUGR对脂肪酸加工的影响然而，IUGR羊有一种倾向， 对照羊，表明脂质处理也可能被胎盘功能不全改变。脂质改变 由于能量产生的改变，子宫内处理可能对心脏功能产生终身影响。 本项目的目的是确定脂肪酸代谢是否受到胎盘功能不全的影响 使用绵羊脐胎盘栓塞模型。参与脂肪酸摄取的机制， 将使用一系列技术系统地检查代谢，包括活细胞成像，脂质组学， 线粒体应激试验和基因和蛋白质表达分析。这项研究将确定如何 产前应激改变心肌细胞代谢，可能指导未来改善营养的治疗 实践和/或心血管健康。