Omega 3 Fatty Acids Acute Neuroprotection via Mitochondria

Omega 3 脂肪酸通过线粒体提供急性神经保护作用

基本信息

批准号：
9450547
负责人：
RICHARD JOSEPH DECKELBAUM
金额：
$ 35万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9450547
关键词：
Acute Address Affect Aftercare Apoptosis Apoptotic Attenuated BAX gene Blood Brain Brain Death Brain Injuries Cardiovascular Diseases Caspase Cause of Death Cell Death Cell Membrane Structures Cell Survival Cell membrane Cells Cerebrum Child Complex Disabled Persons Docosahexaenoic Acids Dose Eicosapentaenoic Acid Elements Emulsions Exposure to Failure Fatty Acids Generations Glucose Habits Human Hypoxic-Ischemic Brain Injury In Vitro Injections Injury Intravenous Ischemia Laboratories Life Style Link Lipids Liver Measures Membrane Membrane Structure and Function Mitochondria Mitochondrial Matrix Morbidity - disease rate Mus Myocardial Infarction Neonatal Neurologic Neurons Nonesterified Fatty Acids Omega-3 Fatty Acids Omega-6 Fatty Acids Outcome Outer Mitochondrial Membrane Oxidative Stress Oxygen Pathway interactions Permeability Production Radiolabeled Reactive Oxygen Species Recovery Reperfusion Therapy Research Personnel Rodent Role Severities Societies Specificity Stroke Testing Triglycerides attenuation cell injury clinical application cytochrome c deprivation dosage experimental study fatty acid transport improved in vivo mitochondrial dysfunction mitochondrial membrane mortality natural hypothermia neonatal brain neonate neuroprotectin D1 neuroprotection novel oxidation oxidative damage particle prevent pro-apoptotic protein public health relevance transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Hypoxic-ischemic brain injury (HI) is the major cause of permanent neurological handicap in children. Omega- 3 (n-3) fatty acids (FA), especially eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), have emerged as major elements for cell membrane structure+-function. n-3 FA beneficially alter outcomes of hypoxic-ischemic brain injury in rodents. The investigators' laboratories are demonstrating that acute injectio of intravenous triglyceride (TG) emulsions enriched in DHA and EPA markedly protect rodent brains against HI injury after HI in neonatal mice. Emulsions with TG containing only DHA (triDHA) showed major neuroprotective effects, and this was not shared by emulsions containing only triEPA or n-6 TG. The neuroprotection shown by triDHA occurred when injected even at 2hr after reperfusion. Neuroprotection was associated with 1) increased brain content of neuroprotectin D1 (NPD1), 2) increased DHA in cerebral mitochondria, and 3) attenuation of mitochondrial membrane permeabilization after HI. Our overall hypothesis is that triDHA changes mitochondrial FA composition and preserves mitochondrial function after HI by limiting Ca2+ induced membrane permeabilization, a central mechanism of cell death after ischemia. A key component of our hypothesis is that beneficial effects of triDHA relate to decreasing reactive oxygen species (ROS) surges in mitochondria, limiting mitochondrial self-oxidation, thereby preserving mitochondrial membrane integrity. These hypotheses will be tested under three Specific Aims. Aim 1 will characterize how n-3 TG and their catabolites are delivered to neonatal brain after acute injection following HI injury and determine optimal dosages and FA specificity for maximum neuroprotection and compare this with hypothermia treatment. We anticipate that after injection triDHA is first taken up by liver and after repackaging into TG or FA, and/or partially catabolized to NPD1 to reach brain to promote neuroprotection. In Aim 2 we will determine whether n- 3 TG treatment after HI modifies mitochondrial FA composition and how this alleviates secondary mitochondrial dysfunction in reperfusion. We expect these experiments will confirm a major role for DHA in protecting mitochondria by decreasing mitochondrial generation of ROS, a major factor for injury to mitochondria and cells. Aim 3 will determine whether DHA-associated neuroprotection relates to increased production of NPD1 through its anti-apoptotic effects. The focus will be on the role of NPD1 interacting with mitochondria to prevent permeabilization of outer mitochondrial membranes and whether this involves translocation of anti-apoptotic pathways.

描述（由应用提供）：缺氧 - 缺血性脑损伤（HI）是儿童永久性神经系统障碍的主要原因。 Omega-3（N-3）脂肪酸（FA），尤其是eicosapentaenoic（EPA）和Docosahecahexaenoic Acid（DHA）已成为细胞膜结构+功能的主要元素。 N-3 FA有益地改变啮齿动物中缺氧 - 缺血性脑损伤的结局。研究人员的实验室表明，在新生儿小鼠的新生儿小鼠中，富含DHA和EPA的急性注射富含DHA和EPA的静脉注射液体（TG）乳液在HI上受到HI损伤。仅包含DHA（TRIDHA）的TG乳液显示出主要的神经保护作用，仅包含Triepa或N-6 TG的乳液并不共同。当再灌注后2小时注射时，TRIDHA所示的神经保护作用。神经保护与1）神经保护素D1（NPD1）的脑含量增加有关，2）HI后脑部线粒体膜通透性的DHA增加。我们的总体假设是，Tridha通过限制Ca2+诱导的膜通透性（一种缺血后细胞死亡的中心机制），改变了HI后HI后线粒体功能的线粒体功能。关键目标1将表征HI损伤后急性注射后N-3 TG及其分解代谢物如何递送到新生儿大脑中，并确定最佳剂量和FA特异性，以最大程度地进行神经保护，并将其与体温过低治疗进行比较。我们预计，在注射后，Tridha首先被肝脏和重新包装到TG或FA之后和/或部分分解为NPD1以促进神经保护作用。在AIM 2中，我们将确定HI后N-3 TG治疗是否修饰了线粒体FA组成，以及该如何减轻再灌注中的次级线粒体功能障碍。我们预计这些实验将通过降低线粒体的ROS来保护DHA在保护线粒体中的主要作用，这是线粒体损伤和细胞损伤的主要因素。 AIM 3将确定与DHA相关的神经保护关系是否通过其抗凋亡作用来增加NPD1的产生。重点将放在NPD1与线粒体相互作用以防止线粒体膜透化的作用，以及这是否涉及抗凋亡途径的易位。