Uncontrolled inflammation is considered a unifying pathology of a wide range of diseases including sepsis, cancer, and vascular diseases, among others. Infectious diseases such as sepsis remain an unmet clinical challenge with high mortality and increasing incidents despite the advances in modern medicine. Phagocytes play critical role during acute inflammation by controlling host defense mechanisms, via temporal regulation of classical pro-inflammatory eicosanoids and the production specialized pro-resolving mediators (SPMs) that include Resolvins, Protecting and Maresins elucidated by the Sponsor and his Laboratory. SPM are sub- nanomolar potent, stereoselective agonists that promote microbial clearance, containing, and while enhancing host survival by accelerating resolution mechanisms of inflammation as thus serve as immunoresolvents. The bone marrow (BM) is a critical organ that generates and mobilizes phagocytes in response to invading pathogens. This proposal is based on new findings from work in progress, where we identify a specific clusters of SPM in human BM and BM from mice with remote peritoneal infections, which includes Maresin 1 (MaR1), Resolvin D1 (RvD1), Resolvin D3, and Lipoxin B4 (LXB4), using state-of-the-art metabololipidomics profiling approach. To this date, the functional role(s) of SPMs in the bone marrow are uncharted. We proposed to test the following hypothesis: Specialized pro-resolving mediators (SPM) produced within the bone marrow during infections at distant sites, tightly regulate hematopoietic (i.e. myelopoiesis) signals that are required for the resolution of infectious inflammation and microbial clearance. To address this following aims are proposed using human BM tissue and murine models of infection. We will examine: 1) the temporal relationship(s) between SPM and classical pro-inflammatory eicosanoids in BM cells during local and systemic infections, 2) the functional role(s) of BM Pro-resolving mediators in hematopoietic cells and 3) cell-specific intracellular signaling circuits of pro-resolving mediators in healthy human BM cells. The proposed research project, career development and mentorship of Dr. Stephania Libreros by her sponsor Dr. Charles N. Serhan and the scientific advisory committee would allow her a successful completion of this proposal. Results from these studies will provide fundamental new insights into the functions of SPMs and novel pro-resolving pathways in the BM during infection that can help clinicians approach new treatments for infectious-inflammation by stimulating endogenous resolution mechanisms.
Acute inflammation is a protective mechanism used by the body to eradicate invading pathogens. Specialized Pro-resolving Mediators (SPMs) are new endogenous chemical mediators that stimulate resolution of infection and the body own anti-microbial mechanisms. We propose a research plan to determine the functional role of SPMs in the bone marrow during systemic infections, with the ultimate goal to identify novel pro-resolving pathways involved in resolving diseases associated with infectious inflammation. !
