Impact of Prenatal Hypoxia on Mitochondrial Function of Offspring Hearts

产前缺氧对子代心脏线粒体功能的影响

基本信息

批准号：
10218255
负责人：
LOREN P THOMPSON
金额：
$ 52.92万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218255
关键词：
ATP Synthesis Pathway Adenine Nucleotides Adult Adult Children Adverse event Affect Aging Apoptosis Attention Bioenergetics Biogenesis Blood Vessels Cardiac Cardiovascular Physiology Cause of Death Cavia Cell membrane Cells Characteristics Chronic Complex Confocal Microscopy Consumption Data Deterioration Development Disease Echocardiography Energy Metabolism Equilibrium Ethnic group Etiology Exhibits Exposure to Face Failure Female Fetal Development Fetal Growth Fetal Growth Retardation Fetal Heart Fetus Functional disorder Gene Expression Generations Glycolysis Goals Growth Growth and Development function Health Health Care Costs Heart Heart Diseases Heart Mitochondria Heart Ventricle Heart failure Hypertension Hypoxemia Hypoxia Image Impairment Inflammation Knowledge Life Link Measures Membrane Membrane Potentials Messenger RNA Metabolic syndrome Mitochondria Mitochondrial Proteins Molecular Target Morphology Myocardial dysfunction NADH Niacinamide Organ Oxidation-Reduction Oxidative Phosphorylation Oxygen PPAR Pathway Pathology Pathway interactions Pharmacology Pharmacotherapy Phase Phenotype Play Pregnancy Premature aging syndrome Prenatal care Process Regulation Research Resolution Respiration Respiratory Chain Respiratory physiology Resveratrol Risk Role Signal Transduction Sirtuins Stimulus Stress Stroke Structure Suggestion Transcriptional Regulation Treatment Protocols Ventricular Dysfunction Ventricular Function Woman cardioprotection complex IV cytochrome c oxidase disorder risk fatty acid oxidation fetal heart cell heart disease risk heart function improved in utero in vivo intrauterine environment live cell imaging men mitochondrial dysfunction mitochondrial membrane mortality risk neonate nicotinamide-beta-riboside novel strategies offspring perinatal period porcine model postnatal pregnant prenatal prenatal exposure pressure prevent programs protein expression public health relevance respiratory response sexual dimorphism

项目摘要

Project Summary Adverse events occurring during fetal life can contribute to an increased risk of disease in adult life. Chronic intrauterine hypoxia causes fetal growth restriction and renders the offspring vulnerable to hypertension and heart disease as well as other complications. Thus, the developmental origins of health and disease (DOHaD) hypothesis has posited a critical role of prenatal care in etiologies of several disease conditions. Prenatal hypoxia has been shown to disrupt cardiovascular function through mechanisms associated with both heart and blood vessel pathologies. We have generated a well established hypoxic pregnant guinea pig model that exhibits fetal and offspring phenotype of mitochondrial dysfunction. Further, our data show that exposure to hypoxia during the fetal growth phase inhibits contractile function in the offspring heart. We propose that mitochondrial-specific mechanisms associated with biogenesis and bioenergetics in the fetal heart are inhibited, which is sustained in the offspring and manifest as cardiac ventricular dysfunction. We will determine the effects of prenatal hypoxia on mRNA/gene expression of the PGC1a/PPAR pathway and respiratory chain complex expression in fetal hearts. We will evaluate the sustained consequences of prenatal hypoxia on mitochondrial respiration in intact cardiac cells. Using live cell imaging with super-resolution confocal microscopy, we will identify the effects of prenatal hypoxia on mitochondrial structure, membrane integrity, and Ca2+ transients in cell contraction of cardiac cells from offspring hearts. We will evaluate ventricular dysfunction in the offspring hearts exposed to prenatal hypoxia by echocardiography and pressure-volume loop analysis. Finally, we will treat pregnant sows and neonates with nicotinamide modulators (resveratrol and nicotinamide riboside) to enhance the NAD+/NADH ratio, which is a central regulator of energy metabolism. We will determine whether treatment enhances mitochondrial function and/or contractile function of the offspring as a pharmacological approach for improving mitochondrial health and reducing the risk of heart disease.

项目概要胎儿时期发生的不良事件可能会增加成年后患病的风险。慢性宫内缺氧会导致胎儿生长受限，使后代容易患高血压、心脏病以及其他并发症。因此，健康与疾病的发育起源（DOHaD）假说提出了一个关键的假设：产前护理在多种疾病病因中的作用。产前缺氧已被证明会破坏通过与心脏和血管病理相关的机制来发挥心血管功能。我们已经生成了一个完善的缺氧怀孕豚鼠模型，表现出胎儿和后代线粒体表型功能障碍。此外，我们的数据表明，胎儿生长阶段暴露于缺氧会抑制胎儿的收缩功能。子孙之心。我们提出与生物发生和生物能学相关的线粒体特异性机制胎儿心脏受到抑制，这种抑制在后代中持续存在，表现为心室功能障碍。我们将确定产前缺氧对 PGC1a/PPAR 通路和呼吸链 mRNA/基因表达的影响胎儿心脏的复杂表达。我们将评估产前缺氧对线粒体的持续影响完整心肌细胞的呼吸。使用超分辨率共聚焦显微镜的活细胞成像，我们将识别产前缺氧对线粒体结构、膜完整性和细胞收缩过程中 Ca2+ 瞬变的影响来自后代心脏的心肌细胞。我们将评估暴露于产前的后代心脏的心室功能障碍通过超声心动图和压力-容量环分析进行缺氧。最后，我们将用以下药物治疗怀孕母猪和新生儿：烟酰胺调节剂（白藜芦醇和烟酰胺核苷）可提高 NAD+/NADH 比率，这是一个核心能量代谢调节剂。我们将确定治疗是否增强线粒体功能和/或收缩功能后代的功能作为改善线粒体健康和降低心脏病风险的药理学方法疾病。