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Perinatal cardiomyocyte pruning driven by metabolic maturation: Opportunity for intervention

代谢成熟驱动的围产期心肌细胞修剪：干预机会

基本信息

批准号：
10566503
负责人：
Sonnet Sky Jonker
金额：
$ 1.63万
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：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10566503
关键词：
Address Adult Age Air Animal Model Antioxidants Apoptosis Apoptotic Automobile Driving Autophagocytosis Birth Brain Breathing Carbohydrates Cardiac Cardiac Myocytes Cardiac health Caspase Cell Count Cell Death Cells Cessation of life Childhood Clinical Trials Complex Congenital Heart Defects Data Defect Depressed mood Development Diet Disease Endowment Environment Enzymes Event Face Fatty acid glycerol esters Female Fetal Growth Retardation Fetal Heart Fetus Gene Expression Generations Genus Hippocampus Growth Heart Heart Abnormalities Heart Diseases Heart failure Human Hypoxemia Hypoxia Individual Infant Intervention Knowledge Lead Life Life Stress Mammals Measures Mediating Medical Melatonin Metabolic Metabolic Pathway Metabolism Milk Muscle Cells Myocardium Normal Cell Operative Surgical Procedures Oxidative Stress Oxygen Pathologic Pathology Pathway interactions Perinatal Physiological Physiology Placenta Pregnancy Premature Birth Preparation Process Progressive Disease Public Health Pump Reactive Oxygen Species Respiration Risk Risk Factors Role Sheep Signal Pathway Signal Transduction Stress Testing Therapeutic Thyroid Hormones Time Tissues United States Uterine Contraction Ventricular Work antioxidant therapy base congenital heart disorder design effective therapy experience fatty acid metabolism fetal fetus hypoxia heart function hemodynamics high risk infant improved in utero innovation interest male melatonin supplementation neuroprotection novel strategies oxidative damage perinatal period postnatal postnatal period premature prenatal prevent sex stem cell therapy translational model

项目摘要

Project Summary Cardiac myocyte number is a fundamental determinant of heart function which, due to progressive cell loss, becomes especially important when the heart is stressed, such as when there is pediatric or adult heart disease. Although intensive medical effort is focused on sparing myocytes during the disease process and there is intense (as-yet unrealized) interest in restoring numbers through stem cell therapies, no work has been done to address the large perinatal loss of cardiac myocytes. This is a therapeutic opportunity to increase life-long cardiac myocyte number substantially. What is not known are the exact timing of the cell loss in the peripartum period, and the signals in the near-birth cardiac milieu driving the cell loss. In the same window during which myocyte loss occurs, the fetus faces increasing hypoxia, the fetal heart undergoes metabolic maturation in preparation for the high-fat milk diet to come immediately after birth, and thyroid hormone increases many-fold. The interaction of these three factors likely contribute to cardiac myocyte loss via oxidative stress and apoptosis. Further, male fetuses are notable for having “risky” in utero growth strategies which may lead to increased sensitivity to pathological developmental programming. We suspect that the interactions of these signaling pathways render hearts susceptible before birth, but that oxidative stress and cell death can be suppressed by an antioxidant. In this study we will use a large animal model (sheep) to examine both isolated (in culture) effects of these regulators on metabolism and apoptosis, as well as their role in the more complex in utero environment. We will use the Seahorse Bioanalyzer to measure cardiomyocyte respiration with different metabolic substrates and under different test conditions. We will also measure cell death, as assessed by cell number, enzyme release and activity, and apoptotic and autophagic pathway activation. We will tie these results in to reactive oxygen species generation and activation of cell death pathways. We will also determine if melatonin supplementation to reduce oxidative stress prevents the near-term loss of cardiac myocyte number. Significance: Heart failure can be reduced by increasing the number of healthy cardiac myocytes. Myocyte endowment is substantially reduced around the time of birth in an event that represents a powerful opportunity for intervention. We aim to increase myocyte number at birth by targeting the connection between metabolic maturation, hypoxia and cell loss in a translational model applicable to human physiology.

项目摘要心肌细胞数量是心脏功能的基本决定因素，由于进行性细胞损失，当心脏受到压力时，例如儿童或成人心脏病时，这一点变得尤为重要。尽管密集的医疗努力集中在疾病过程中保留肌细胞，并且存在强烈的免疫缺陷。（尚未实现）通过干细胞疗法恢复数量的兴趣，没有做任何工作来解决围产期心肌细胞大量丢失。这是一个治疗的机会，以增加终身心脏肌细胞数量显著增加。不知道的是围产期细胞损失的确切时间，以及临近出生时心脏环境中的信号导致细胞丢失。在心肌细胞丢失的同一时间窗内，胎儿面临着日益严重的缺氧，经历代谢成熟，为出生后立即开始的高脂肪牛奶饮食做准备，甲状腺激素会增加很多倍这三个因素的相互作用可能有助于心肌细胞通过氧化应激和细胞凋亡的损失。此外，男性胎儿在子宫内的生长是有“风险”的这些策略可能导致对病理发育编程的敏感性增加。我们怀疑这些信号通路的相互作用使心脏在出生前易受影响，但氧化应激和细胞死亡可以被抗氧化剂抑制。在这项研究中，我们将使用一个大型动物模型（绵羊）来检查这两个孤立的（在文化）的影响，代谢和细胞凋亡的调节因子，以及它们在更复杂的子宫内环境中的作用。我们将使用Seahorse生物分析仪测量具有不同代谢底物的心肌细胞呼吸，在不同的测试条件下。我们还将测量细胞死亡，通过细胞数量、酶释放和活性，以及凋亡和自噬途径激活。我们将把这些结果与活性氧联系起来物种生成和细胞死亡途径的激活。我们还将确定是否补充褪黑激素减少氧化应激可防止心肌细胞数量的近期损失。意义：心力衰竭可以通过增加健康心肌细胞的数量来减少。肌细胞在出生时，禀赋会大幅减少，这是一个强大的机会，进行干预。我们的目标是增加出生时的肌细胞数量，适用于人类生理学的转化模型中的成熟、缺氧和细胞损失。