Fatty Acids: Ischemic Protection and Repair

脂肪酸：缺血保护和修复

基本信息

批准号：
9473106
负责人：
Ira J Goldberg
金额：
$ 59.45万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9473106
关键词：
Acute Affect Aging Animals Blood flow CD36 gene CD95 Antigens Cardiac Cardiac Myocytes Cells Chronic Collaborations Defect Diglycerides Disease Energy Metabolism Fatty Acids Funding Gene Deletion Genes Glucose Heart Heart Injuries Heart failure Histology Human Hydrolysis Hypertriglyceridemia Impairment In Vitro Infarction Inflammation Injury Investigation Ischemia Kinetics Laboratories Lasers Lead Leukocytes Lipids Lipolysis Lipoproteins Metabolic Metabolism Methods Microscopy Modeling Mus Myelogenous Myeloid Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Myosin Heavy Chains Nonesterified Fatty Acids Nonmuscle Myosin Type IIA Obesity Oxygen PPAR alpha PPAR gamma Paper Pathway interactions Phenotype Process Production Radioactive Reperfusion Therapy Research Design SLC2A1 gene Source Stress Testing Time Tissues Toxic effect Tracer Transferase Transgenic Organisms Triglycerides Work cardiac repair clinically relevant deprivation experimental study fatty acid metabolism fatty acid oxidation glucose metabolism glucose uptake heart function improved in vivo injury and repair lipid metabolism lipoprotein lipase macrophage novel strategies oxidation oxidized lipid prevent receptor repaired response uptake

Acute Affect Aging Animals Blood flow CD36 gene CD95 Antigens Cardiac Cardiac Myocytes Cells Chronic Collaborations Defect Diglycerides Disease Energy Metabolism Fatty Acids Funding Gene Deletion Genes Glucose Heart Heart Injuries Heart failure Histology Human Hydrolysis Hypertriglyceridemia Impairment In Vitro Infarction Inflammation Injury Investigation Ischemia Kinetics Laboratories Lasers Lead Leukocytes Lipids Lipolysis Lipoproteins Metabolic Metabolism Methods Microscopy Modeling Mus Myelogenous Myeloid Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Myosin Heavy Chains Nonesterified Fatty Acids Nonmuscle Myosin Type IIA Obesity Oxygen PPAR alpha PPAR gamma Paper Pathway interactions Phenotype Process Production Radioactive Reperfusion Therapy Research Design SLC2A1 gene Source Stress Testing Time Tissues Toxic effect Tracer Transferase Transgenic Organisms Triglycerides Work cardiac repair clinically relevant deprivation experimental study fatty acid metabolism fatty acid oxidation glucose metabolism glucose uptake heart function improved in vivo injury and repair lipid metabolism lipoprotein lipase macrophage novel strategies oxidation oxidized lipid prevent receptor repaired response uptake

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项目摘要

The heart reduces fatty acid (FAs) oxidation and switches to greater glucose utilization with ischemia. While this process allows more ATP production with less oxygen use, it occurs at the expense of limiting the use of FAs, the major substrates for cardiac energy. We hypothesize that this leads to fuel deprivation, especially as blood flow reduction decreases energetic substrate availability. If this hypothesis is correct, then storage of more triglyceride in the heart would lead to reduced ischemic damage; this we speculate is the reason for the “obesity paradox” in which obese humans who have more ischemic disease also have increased post myocardial infarction survival. This proposal includes experiments to study basic and clinically relevant relationships between heart FA metabolism and heart function. Specifically, we will use mice created by the PI to study how changes in triglyceride stores and lipid uptake alter cardiac response to ischemia/reperfusion. In addition, we will test whether deletion of genes required for normal uptake of FAs by myeloid cells affects their conversion to an alternatively activated and reparative phenotype. These studies will include assessment of cardiac gene changes and lipidomics and will utilize tracer kinetics to assess uptake and oxidation of glucose and lipids, and to determine their downstream products. The experiments will require the collaboration of two laboratories: one with expertise in heart lipid metabolism and the second with expertise in ischemic/reperfusion models and analysis of substrate metabolism. The three aims of this application are the following: Aim 1. To determine whether increased cardiomyocyte storage of triglyceride improves response to ischemia. Aim 2. To assess whether mice with reduced heart lipid uptake have altered response to ischemia. Aim 3. To assess ischemic injury and repair in mice with macrophage-specific deletions of lipoprotein lipase and cluster of differentiation (CD)36. The experiments will use several lines greater cardiac triglyceride stores due to transgenic expression of diacylglycerol acyl transferase 1 and peroxisomal proliferator activated receptor γ, and mice with reduced uptake of FAs due to tissue specific deletions of lipoprotein lipase and CD36. These studies will illustrate possible metabolic approaches to reducing ischemic injury and improving repair of damaged myocardium.

心脏减少脂肪酸（FAS）氧化，并通过缺血转换为更大的葡萄糖利用。尽管此过程允许使用更少的氧气产生更多的ATP生产，以牺牲限制使用 FAS，心脏能量的主要底物。我们假设这导致了剥夺燃料的剥夺，尤其是血流减少可降低能量基质的可用性。如果此假设正确，则存储心脏中更多的甘油三酸酯会导致缺血性损害降低。我们推测的是 “肥胖悖论”，其中有更多缺血性疾病的肥胖人也增加了心肌梗死生存。该建议包括研究心脏之间基本和临床相关关系的实验 FA代谢和心脏功能。具体来说，我们将使用PI创建的小鼠研究如何变化甘油三酸酯存储和脂质摄取改变心脏对缺血/再灌注的反应。此外，我们将测试髓样细胞正常摄取FA所需的基因是否会影响其转化为替代激活和修复表型。这些研究将包括对心脏基因的评估变化和脂肪组学，并将利用示踪剂动力学评估葡萄糖和脂质的摄取和氧化，以及确定其下游产品。实验将需要两个实验室的合作：一个具有心脏脂质代谢方面的专业知识，第二个具有缺血/再灌注模型的专业知识，底物代谢的分析。该应用程序的三个目标是：目标1。确定甘油三酸酯的心肌细胞储存是否增加可以改善对缺血的反应。目标2。评估心脏脂质摄取减少的小鼠是否对缺血的反应改变了。目标3。评估缺血性脂肪蛋白脂肪酶的巨噬细胞特异性缺失和分化簇的损伤和修复（CD）36。由于转基因表达二酰基甘油酰基转移酶1和过氧化物体增生剂激活受体γ，而小鼠则减少由于组织特异性缺失的脂蛋白脂肪酶和CD36的吸收。这些研究将说明减少缺血性损伤和改善受损心肌修复的可能代谢方法。