Mechanism of action of omega-3 fatty acids in brain injury

描述(申请人提供)：公众利益导致作为膳食补充剂(主要来自鱼油)的omega-3脂肪酸消费量增加，其据称的效果包括：降低心血管疾病和死亡率，减少脑血管疾病和中风，保护视力，以及减缓衰老过程中的认知衰退。在过去的几年里，对omega-3脂肪酸及其对健康影响的科学审查有了戏剧性的增加。结果表明，omega-3脂肪酸具有很强的抗炎作用。炎症是许多慢性疾病的根源，包括冠心病、糖尿病、关节炎、肥胖症、黄斑变性、干眼、骨质疏松症、阿尔茨海默病和精神健康疾病，临床和实验研究表明，omega-3脂肪酸具有预防和治疗作用。Omega-3脂肪酸(尤其是二十二碳六烯酸-DHA)是唯一集中在中枢神经系统中的脂肪酸，参与神经保护、认知和其他大脑和视网膜功能。然而，omega-3脂肪酸的作用机制及其对公众健康的意义并不完全清楚。在这一重大机遇中，我们组建了一个由来自互补领域的三名有成就的研究人员组成的团队，为一个新的研究领域--omega-3必需脂肪酸在炎症疾病控制中的信号机制--提供基础。我们将从一个为期两年的合作项目开始，该项目专注于中风半影区的新型omega-3脂肪酸介质，这将使我们对omega-3脂肪酸衍生介质在体内的作用机制有一个新的理解，并将为进一步研究如何利用omega-3脂肪酸来预防或控制其他疾病和紊乱的慢性过程提供指南。综合而言，督导计划具备所有所需的方法和实验室资源，可供即时推行计划之用。这一重大机遇计划是一个大型研究项目，将加速omega-3必需脂肪酸生物学方面的关键突破，并创造尖端技术来生产新型脂质生物活性介质，极有可能在生物医学研发、公共卫生和医疗保健提供方面实现增长和投资。结果将作为初创公司或在老牌制药公司部署的基础。此外，该项目可以使用拟议的两年期资金完成，而不需要在获奖期后继续提供NIH资金。这个项目可以被视为跨NIH的努力，因为它将对NCCAM、NINDS、NHLBI、NIA、NEI和其他机构产生影响。需要解决的具体研究问题是基于这样一个创新概念，即最近发现的DHA衍生介质神经保护素D1(NPD1)和阿司匹林触发的(AT)神经保护素D1(AT-NPD1)可以抑制缺血再灌注介导的白细胞渗透和促炎基因表达，并在卒中半暗带诱导神经保护。由于NPD1和AT-NPD1都是在再灌注损伤过程中产生的，我们的计划包括四个相互关联的研发创新目标，其中包括确定这些DHA衍生物和相关介质在实验性卒中中的潜在协同作用。这些新型介体的分离和表征将作为指导，引导人们对omega-3脂肪酸如何用作补充剂，进而可能用于预防医学的新见解。此外，这些介体的全有机化学合成将是开发新型治疗剂的基础，这些治疗剂将模拟大脑在面对损伤时如何试图保护自己。此外，这些介体在一生中可能被用作新的omega-3脂肪酸生物标记物，特别是在衰老和脑损伤条件下。到目前为止，AT-NPD1途径的组成成分还没有确定，它们的化学合成还没有进行，它们的生物活性也还没有被研究。为了实现我们的目标，我们将使用强大的串联质谱学、药物化学、高分辨率磁共振成像以及大鼠和12/15脂氧合酶(LOX)缺陷小鼠的中风体内实验模型。 公共卫生相关性：这项建议是基于一个创新的概念，即这个由三个主要研究人员组成的项目将发现新的信号，这将改变对omega-3脂肪酸在脑损伤和中枢神经系统中的理解和意义。对新机制和生物标记物的识别可以作为指导，帮助人们深入了解omega-3脂肪酸如何被用作补充剂，进而可能在慢性炎症性疾病和中风中具有预防作用。

DESCRIPTION (provided by applicant): Public interest has resulted in increased consumption of omega-3 fatty acids as dietary supplements (derived mainly from fish-oil) based upon purported effects that include: reduction in cardiovascular morbidity and mortality, reduction in cerebrovascular disease and stroke, preservation of vision, and slowing of cognitive decline during aging. Over the past several years, there has been a dramatic increase in the scientific scrutiny of omega-3 fatty acids and their impact on health. Results indicate that omega-3 fatty acids have potent anti-inflammatory actions. Inflammation is at the root of many chronic diseases, including coronary heart disease, diabetes, arthritis, obesity, macular degeneration, dry eye, osteoporosis, Alzheimer's disease and mental health disorders, and there is evidence from clinical and experimental studies that omega-3 fatty acids are endowed with preventive and therapeutic benefits. Omega-3 fatty acids (docosahexaenoic acid-DHA particularly), are uniquely concentrated in the central nervous system and are involved in neuroprotection, cognition, and other brain and retinal functions. However, the mechanism of action for omega-3 fatty acids and their significance for public health are not completely understood. In this Grand Opportunity, we have assembled a team of three accomplished investigators from complementary fields to propose the foundation for a new field of investigation -- signaling mechanisms of omega-3 essential fatty acids in inflammatory disease control. We will do this by beginning with a collaborative two-year project focused upon novel omega-3 fatty acid mediators at the stroke penumbra that will bring a new understanding to the mechanism of action of omega-3 fatty acid-derived mediators in vivo and will provide guideposts for further studies on how omega-3 fatty acids can be harnessed to prevent or control chronic processes in other diseases and disorders. Together, the PIs have all the required methods and laboratory resources readily available for immediate project implementation. This Grand Opportunity proposal is a large-scale research project that will accelerate critical breakthroughs on the biology of omega-3 essential fatty acids and create cutting-edge technologies to produce novel lipid bioactive mediators, with a high likelihood of enabling growth and investment in biomedical research and development, public health, and health care delivery. Results will serve as the basis for start-up companies or for deployment in established pharmaceutical companies. Moreover, the project can be accomplished using the proposed two years of funds without continued NIH funding beyond the award period. This project can be viewed as a trans-NIH effort because there will be an impact on NCCAM, NINDS, NHLBI, NIA, NEI and others. The specific research question to be tackled is based upon the innovative concept that the recently identified DHA-derived mediators, neuroprotectin D1 (NPD1) and aspirin-triggered (AT)-neuroprotectin D1 (AT-NPD1), inhibit ischemia-reperfusion mediated leukocyte infiltration and pro-inflammatory gene expression, as well as elicit neuroprotection in the stroke penumbra. Since NPD1 and AT-NPD1 are both produced during reperfusion injury, our plan consists of four interrelated Research and Development Innovation goals, which include defining the potential synergism of these DHA derivatives and related mediators in experimental stroke. The isolation and characterization of these novel mediators will serve as a guide leading to new insights on how omega-3 fatty acids can be used as supplements that, in turn, may be used in preventive medicine. Also, the total organic chemical synthesis of these mediators will be the foundation for the development of novel therapeutic agents that will mimic how the brain attempts to protect itself when confronted with injury. In addition, these mediators may be used as novel omega-3 fatty acid biomarkers throughout life, but particularly during aging and in brain injury conditions. As of yet, the components of the AT-NPD1 pathway have not been characterized, their chemical synthesis has not been performed, and their bioactivity has not been studied. To accomplish our objectives, we will use powerful tandem mass spectrometry, medicinal chemistry, high-resolution magnetic resonance imaging, and in vivo experimental models of stroke in rats and 12/15-lipoxygenase (LOX)-deficient mice. Public Health Relevance: This proposal is based upon the innovative concept that this three-Principal Investigator project will uncover novel signaling that will make a difference in the understanding and significance of omega-3 fatty acids in brain injury and the central nervous system. Identification of the new mechanisms and biomarkers could serve as a guide leading to insights on how omega-3 fatty acids could be used as a supplement that, in turn, may possess preventative actions in chronic inflammatory diseases and stroke.