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.
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.
|Bazan, Nicolas G; Eady, Tiffany N; Khoutorova, Larissa et al. (2012) Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp Neurol 236:122-30
|Petasis, Nicos A; Yang, Rong; Winkler, Jeremy W et al. (2012) Stereocontrolled total synthesis of neuroprotectin D1 / protectin D1 and its aspirin-triggered stereoisomer. Tetrahedron Lett 53:1695-1698
|Belayev, Ludmila; Khoutorova, Larissa; Atkins, Kristal D et al. (2011) Docosahexaenoic Acid therapy of experimental ischemic stroke. Transl Stroke Res 2:33-41
|Serhan, Charles N; Petasis, Nicos A (2011) Resolvins and protectins in inflammation resolution. Chem Rev 111:5922-43
|Stark, David T; Bazan, Nicolas G (2011) Synaptic and extrasynaptic NMDA receptors differentially modulate neuronal cyclooxygenase-2 function, lipid peroxidation, and neuroprotection. J Neurosci 31:13710-21
|Serhan, Charles N; Fredman, Gabrielle; Yang, Rong et al. (2011) Novel proresolving aspirin-triggered DHA pathway. Chem Biol 18:976-87
|Bazan, Nicolas G; Molina, Miguel F; Gordon, William C (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu Rev Nutr 31:321-51
|Yang, Rong; Fredman, Gabrielle; Krishnamoorthy, Sriram et al. (2011) Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals. J Biol Chem 286:31532-41
|Krishnamoorthy, Sriram; Recchiuti, Antonio; Chiang, Nan et al. (2010) Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci U S A 107:1660-5
|Fredman, Gabrielle; Van Dyke, Thomas E; Serhan, Charles N (2010) Resolvin E1 regulates adenosine diphosphate activation of human platelets. Arterioscler Thromb Vasc Biol 30:2005-13