A key characteristic of the specialized pro-resolving mediators (SPM), including the resolvins, protectins and the recently identified maresins, is that all of these molecules tend to exhibit an exquisite structure/function proflle, i.e. the close relationship between their potent, receptor-specific, and specialized biological actions with the stereochemistry and substitution patterns of their molecular structures. Consequently, the complete structural characterization and biological study of these new mediators requires the production of isomerically pure materials of known stereochemistry, that can only be obtained via expert total organic synthesis. In our prior efforts we have developed chemical methodologies and strategies for the preparation of a range of SPM derived from polyunsaturated fatty acids. These SPM are characterized by key stereochemical features, including Z/E double bond geometry and R/S stereochemistry, that requires specialized synthetic approaches. The preparation ofthese often labile molecules in stereochemically pure form is essential for the in-depth investigation of their biological profiles. This Project will investigate and validate the following hypothesis: The most potent, endogenously produced, and biologically relevant SPM are produced in stereocontrolled manner by specialized biosynthetic pathways involving key epoxide intermediates. Moreover, the potent biological pro-resolving actions of the resolvins, protectins and maresins, are stereospecific in nature and are associated with certain stereochemical features ofthese molecules.
The specific aims of this Project are: (1) Establish the complete structure and stereochemistry of new SPM. The stereocontrolled synthesis of selected isomerically pure isomers of new resolvins, maresins, and other newly discovered SPM will be pursued, and their structures and properties will be compared with those of biogenic compounds. (2) Elucidate the biosynthetic oathwavs of new SPM. The detailed biosynthetic pathways ofthe maresins, the resolvins and related SPM, will be investigated by employing a stereocontrolled strategy for the synthesis of likely biosynthetic epoxide intermediates, which will be utilized as biosynthetic precursors. (3) Investigate the stereospecific bioloaical actions of new SPM. In collaboration with the other Projects and Cores, the structural features required forthe potent pro-resolving properties ofthese SPM will be established, leading to new approaches for treating diseases involving inflammation and tissue injury.

Public Health Relevance

The findings and materials generated by the proposed studies in this Project will provide the key molecular information and the required synthetic compounds for establishing the important roles of several new specialized pro-resolving mediators in inflammation-resolution pathways. Ultimately, these studies will also help identify fundamentally new and improved therapeutic approaches for treating a variety of conditions involving inflammation and tissue injury, leading to improvements in patient care and unmet medical needs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM095467-01
Application #
8081983
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (CP))
Project Start
Project End
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$308,737
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Serhan, Charles N; Chiang, Nan; Dalli, Jesmond (2017) New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol Aspects Med :
English, Justin T; Norris, Paul C; Hodges, Robin R et al. (2017) Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics. Prostaglandins Leukot Essent Fatty Acids 117:17-27
Norris, Paul C; Libreros, Stephania; Chiang, Nan et al. (2017) A cluster of immunoresolvents links coagulation to innate host defense in human blood. Sci Signal 10:
Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288
Flitter, Becca A; Hvorecny, Kelli L; Ono, Emiko et al. (2017) Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. Proc Natl Acad Sci U S A 114:136-141
Chiang, Nan; Serhan, Charles N (2017) Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Aspects Med 58:114-129
Fredman, Gabrielle; Spite, Matthew (2017) Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 58:65-71
Hansen, Trond Vidar; Dalli, Jesmond; Serhan, Charles N (2017) The novel lipid mediator PD1n-3 DPA: An overview of the structural elucidation, synthesis, biosynthesis and bioactions. Prostaglandins Other Lipid Mediat 133:103-110
Laan, Lisa C; Williams, Andrew R; Stavenhagen, Kathrin et al. (2017) The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 31:719-731

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