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

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.

心脏会减少脂肪酸 (FA) 氧化，并在缺血时提高葡萄糖利用率。这个过程可以用更少的氧气产生更多的 ATP，但其代价是限制使用 FAs是心脏能量的主要底物，我们努力避免这会导致燃料匮乏，尤其是在这种情况下。如果这个假设是正确的，那么血流量的减少会降低能量底物的可用性。心脏中更多的甘油三酯会导致缺血性损伤减少；我们推测这就是造成这种情况的原因。 “肥胖悖论”，即患有更多缺血性疾病的肥胖者在术后的发病率也会增加心肌梗塞生存率。该提案包括研究心脏之间的基本和临床相关关系的实验具体来说，我们将使用 PI 创造的小鼠来研究 FA 代谢和心脏功能的变化。甘油三酯储存和脂质摄取改变心脏对缺血/再灌注的反应。髓样细胞正常摄取 FA 所需的基因缺失是否会影响它们向这些研究将包括心脏基因的评估。变化和脂质组学，并将利用示踪动力学来评估葡萄糖和脂质的摄取和氧化，以及确定其下游产品的实验需要两个实验室的合作：其中之一。具有心脏脂质代谢方面的专业知识，第二个具有缺血/再灌注模型方面的专业知识和该应用的三个目的如下：目的 1. 确定目标 2. 评估心肌细胞储存甘油三酯的增加是否可以改善对缺血的反应。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。巨噬细胞特异性删除脂蛋白脂肪酶和分化簇的小鼠的损伤和修复 (CD)36。由于转基因表达，实验将使用几个具有更高心脏甘油三酯储存的品系。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，以及小鼠的表达减少这些研究将说明由于脂蛋白脂肪酶和 CD36 的组织特异性缺失而导致的 FA 摄取。减少缺血性损伤和改善受损心肌修复的可能代谢方法。