New regulators of lipid metabolism in immature cardiomyocytes

未成熟心肌细胞脂质代谢的新调节因子

基本信息

批准号：
10434904
负责人：
Sonnet Sky Jonker
金额：
$ 69.26万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434904
关键词：
Adverse effects Aerobic Affect BODIPY Biochemical Birth Blood Breast Cardiac Myocytes Cardiovascular Diseases Cause of Death Cells Cessation of life Chronic Complex Data Development Diabetes Mellitus Environment Epidemic Exposure to Fatty Acids Fetal Heart Fetus Genes Genetic Processes Glucose Glycolysis Growth Heart Heart Diseases Heart failure Human Impairment In Vitro Infant Investigation Knowledge Label Laboratories Life Lipids Metabolic Metabolism Mitochondria Molecular Monitor Monounsaturated Fatty Acids Muscle Cells Neonatal Newborn Infant Nonesterified Fatty Acids Nutrition Therapy Obesity Oleic Acids Oxidative Phosphorylation Oxygen Consumption Palmitic Acids Pathologic Pathway interactions Physiological Processes Placental Insufficiency Plasma Pre-Eclampsia Pregnant Women Premature Infant Preparation Process Production Protons Research Research Project Grants Resistance Role Sheep Testing Thyroid Hormones Thyronines Time Toxic effect Tracer Triglycerides Umbilical Cord Blood carbohydrate metabolism cardiogenesis cell injury cost design diabetic epidemiology study experimental study fatty acid analog fatty acid oxidation feeding fetal fetal blood heart cell in vivo lipid metabolism lipidomics long chain fatty acid neglect neonate oxidation postnatal premature sheep model transcription factor transcriptome sequencing uptake

项目摘要

Project Summary In normal babies, plasma lipid levels remain relatively low until birth. Thereafter, they rise dramatically with the onset of breast or formula feeding. By the time a baby is born full term, his or her cardiomyocytes have generated the biochemical machinery to metabolize long chain fatty acids for generating ATP through β- oxidation and oxidative phosphorylation and they are no longer susceptible for lipid toxicity. However, it appears that high levels of lipid can be toxic to immature cells. Unfortunately, there are no studies of lipotoxicity in immature cardiomyocytes. This gap is important for two reasons: 1) pregnant women who are obese, diabetic or have preeclampsia have higher than normal triglycerides and higher than normal free fatty acids. As a consequence, the cord blood of babies also has elevated levels of these lipids. 2) premature babies are often given a commercial lipid preparation with high levels of fatty acids and other complex lipids. In both cases, immature heart cells are exposed to pathologically high lipid levels. This application is designed to determine the vulnerability of developing ovine cardiomyocytes to lipid levels seen in pregnant women with compromising conditions. The purpose of this application is to understand two understudied features of heart development: 1) How cardiomyocyte metabolism can be detrimentally affected by its lipid environment before and after birth and 2) how the metabolic maturation process in cardiomyocytes is regulated by three powerful influences that remain unstudied in the context of lipid metabolism. Thus, our global hypothesis is that 1) immature cardiomyocytes are more vulnerable to abnormal elevations in fetal lipid levels than postnatal myocytes and 2) the maturation of cardiomyocytes is augmented by normal reductions in the expression of the transcription factor, Meis1, and elevations of thyroid hormone levels in the fetal blood and is suppressed by placental insufficiency. Aim 1 will determine the toxic levels of the saturated long chain fatty acid, palmitic acid (PA) and the mono-unsaturated fatty acid, oleic acid (OA) for fetal cardiomyocytes taken from sheep at 100d, 135d, and 14d neonates. In addition, the ability of these cells to take up and store fluorescent long chain fatty acid analogue, BODIPY C-12, will also be determined before and after exposure to high levels of PA and OA. Aim 2 will determine the role of Meis1 in regulating the metabolic transition from glycolysis to oxidative phosphorylation in maturing cardiomyocytes, Aim 3 will determine the degree to which thyroid hormone promotes maturation of cardiomyocytes and resistance to lipotoxicity and Aim 4 will determine the degree to which placental insufficiency stunts maturity of cardiomyocytes and promotes their vulnerability for lipotoxicity. Findings will provide the basis for new studies on human infants to help provide the most helpful fuel mixes for babies who need nutrition therapy and who are born with toxic levels of plasma long chain fatty acids.

项目概要在正常婴儿中，血浆脂质水平在出生之前保持相对较低，此后随着年龄的增长，血浆脂质水平急剧上升。开始母乳喂养或配方奶喂养当婴儿足月出生时，他或她的心肌细胞已经出现。产生了代谢长链脂肪酸的生化机制，通过 β- 产生 ATP 氧化和氧化磷酸化，它们不再对脂质毒性敏感。不幸的是，高水平的脂质似乎对未成熟细胞有毒。未成熟心肌细胞的脂毒性这一差距很重要，原因有两个：1）孕妇。肥胖、糖尿病或患有先兆子痫的人甘油三酯和游离脂肪均高于正常水平因此，婴儿的脐带血中这些脂质的含量也会升高 2) 早产儿。婴儿经常服用含有高含量脂肪酸和其他复杂脂质的商业脂质制剂。在这两种情况下，未成熟的心脏细胞都暴露于病理性高脂质水平。旨在确定发育中的绵羊心肌细胞对妊娠期脂质水平的脆弱性该应用程序的目的是了解两个被研究的女性。心脏发育的特征：1）心肌细胞的代谢如何受到其脂质的令人痛苦的影响出生前后的环境以及2）心肌细胞的代谢成熟过程如何受到脂质代谢背景下尚未研究的三种强大影响的调节。总体假设是 1) 未成熟的心肌细胞更容易受到胎儿脂质异常升高的影响水平高于出生后的心肌细胞，并且2）心肌细胞的成熟通过正常的减少而增强胎儿血液中转录因子 Meis1 的表达和甲状腺激素水平升高并受到胎盘功能不全的抑制。目标 1 将决定饱和长链的毒性水平。胎儿心肌细胞所需的脂肪酸、棕榈酸 (PA) 和单不饱和脂肪酸、油酸 (OA) 取自100天、135天和14天新生儿的羊此外，这些细胞的吸收和储存能力。荧光长链脂肪酸类似物 BODIPY C-12 也将在暴露前后进行测定目标 2 将决定 Meis1 在调节代谢转变中的作用。成熟心肌细胞中糖酵解到氧化磷酸化，目标 3 将确定糖酵解到氧化磷酸化的程度甲状腺激素促进心肌细胞成熟和抗脂毒性，目标 4 将确定胎盘功能不全阻碍心肌细胞成熟并促进其成熟的程度研究结果将为人类婴儿的新研究提供基础，以帮助提供对于需要营养治疗和出生时血浆浓度有毒的婴儿来说最有用的燃料混合物长链脂肪酸。