The elucidation of endogenous pathways and chemical mediators that activate resolution of inflammation is crucial to identify new therapeutic approaches to control excessive inflammation and related diseases. Inflammation and resolution are actively regulated processes, during which a temporal switch in leukocyte populations present in the exudates occurs, likely reflecting changes in bone marrow (BM) hematopoietic stem cells (HSC). Biosynthesis of the specialized pro-resolving lipid mediators (SPM) lipoxin (LX) A4 and resolvin (Rv) D1 also occurs. SPM promote inflammation resolution by regulating leukocyte trafficking as well as the expression of selected microRNAs (miRNAs) via the G-protein coupled receptors (GPCR) FPR2/ALX and GPR32.
Here, we propose to investigate: 1) Whether resolution is regulated at the BM level by specific proresolving miRNAs, whose expression is modulated by LXA4 and RvD1; 2) Which processes are controlled by these miRNAs.
We plan to achieve the outlined specific aims by a system approach to inflammation and resolution. Using self-limited murine peritonitis, we will identify SPM-regulated miRNAs by analyzing temporal changes in the miRNA profile of BM HSC, at resting and upon exposure to LXA4 and RvD1. GPCR-dependence of LXA4 and RvD1 actions will be assessed in experiments with FPR2/ALX or GPR32 recombinant cells. A gain of function approach will be employed to identify target genes of proresolving miRNAs, and assess their roles in HSC differentiation and inflammation. Results from these experiments will help to elucidate key pathways that can be exploited to introduce innovative therapeutic strategies to treat inflammation-related diseases in humans by promoting resolution.
Funding this proposal will reinforce excellence and competitiveness of European research and contribute to the reintegration of the proponent after a period of mobility.
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