The long-term goal of this project is the development of novel regulators of leukocyte function to serve as anti-inflammatory molecules based on the modulation of the mode of action of some new types of lipid-derived mediators (LM). Our recent collaborative work with Dr. Serhan (Project 1) has led to the identification and biological investigation of several new LM that have novel and promising activities, including several biostable analogues of the lipoxins (LX), the aspirin-triggered (ATL) and presqualene disphosphate (PSDP). A typical feature of the above LM is that they are topically active and that they have multi-faceted biological activity, which involves a number of other cell-signaling molecules related to inflammation. Following recent studies that suggested the potential involvement of these LM in periodontal diseases, this project seeks to develop a series of new molecules that would elucidate their role. Thus, this project will pursue the design and synthesis of: (1) new structural analogues of LX and ATL, and (2) new structural analogues of PSDP. In addition to synthetic and conformational studies of these molecules, this project will pursue several new synthetic approaches that may facilitate their synthesis. The synthetic molecules will be used in bioassays in Projects 1-3 of this program and structure-activity relationships will be established for each of the targeted LM. Finally, selected compounds will be scaled-up for in vivo animal model studies in Core D (Demonstration Core). Overall, this project will lead to the elucidation of the physiological and pathophysiological role of several topically active LM, particularly in host defense and inflammation. Therefore, this research may result in development of new molecules with novel anti-inflammatory properties with therapeutic potential in regulation of tissue-mediated injury, as in periodontal disease.
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