Fatty Acids: Ischemic Protection and Repair

脂肪酸：缺血保护和修复

• 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
• 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

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，并在缺血时转换为更大的葡萄糖利用。而 这个过程允许用更少的氧气产生更多的ATP，它是以限制使用 脂肪酸是心脏能量的主要底物。我们假设这会导致燃料匮乏，尤其是 血流减少降低了能量底物的可用性。如果这个假设是正确的，那么存储 心脏中更多的甘油三酯会导致缺血性损伤的减少;我们推测这是 “肥胖悖论”，即患有更多缺血性疾病的肥胖人群也增加了 心肌梗死存活率。 这项建议包括实验研究心脏之间的基本和临床相关的关系 FA代谢和心脏功能。具体来说，我们将使用PI创建的小鼠来研究 甘油三酯储存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 骨髓细胞正常摄取FA所需的基因缺失是否会影响其向 交替激活和修复表型。这些研究将包括评估心脏基因 变化和脂质组学，并将利用示踪动力学评估葡萄糖和脂质的摄取和氧化，以及 以确定其下游产品。这些实验将需要两个实验室的合作： 具有心脏脂质代谢的专业知识，第二个具有缺血/再灌注模型的专业知识， 底物代谢分析。本申请的三个目的如下：目的1.以确定 增加的心肌细胞甘油三酯储存是否改善对缺血的反应。目标2.评估 心脏脂质摄取减少的小鼠是否改变了对缺血的反应。目标3.评估缺血性 巨噬细胞特异性脂蛋白脂酶缺失和分化簇小鼠损伤与修复 （CD）36.实验将使用几个品系，由于转基因表达， 二酰基甘油酰基转移酶1和过氧化物酶体增殖物激活受体γ的表达， 由于脂蛋白脂肪酶和CD 36的组织特异性缺失，FA的摄取。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途径。