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 #
5P01GM095467-02
Application #
8375339
Study Section
Special Emphasis Panel (ZGM1-PPBC-3)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$290,318
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong et al. (2018) Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. Front Pharmacol 9:412
Dalli, Jesmond; Serhan, Charles N (2018) Immunoresolvents signaling molecules at intersection between the brain and immune system. Curr Opin Immunol 50:48-54
Norris, Paul C; Serhan, Charles N (2018) Metabololipidomic profiling of functional immunoresolvent clusters and eicosanoids in mammalian tissues. Biochem Biophys Res Commun 504:553-561
Werz, Oliver; Gerstmeier, Jana; Libreros, Stephania et al. (2018) Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity. Nat Commun 9:59
Colas, Romain A; Ashton, Anthony W; Mukherjee, Shankar et al. (2018) Trypanosoma cruzi Produces the Specialized Proresolving Mediators Resolvin D1, Resolvin D5, and Resolvin E2. Infect Immun 86:
Sham, Ho Pan; Walker, Katherine H; Abdulnour, Raja-Elie E et al. (2018) 15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-?B Regulators in Bacterial Pneumonia. J Immunol 200:2757-2766
Abdulnour, Raja-Elie E; Howrylak, Judie A; Tavares, Alexander H et al. (2018) Phospholipase D isoforms differentially regulate leukocyte responses to acute lung injury. J Leukoc Biol 103:919-932
Halade, Ganesh V; Kain, Vasundhara; Serhan, Charles N (2018) Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure. FASEB J 32:3717-3729
Sorokin, Alexander V; Norris, Paul C; English, Justin T et al. (2018) Identification of proresolving and inflammatory lipid mediators in human psoriasis. J Clin Lipidol 12:1047-1060
Serhan, Charles N; Chiang, Nan; Dalli, Jesmond (2018) New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol Aspects Med 64:1-17

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