While acute inflammation is protective, uncontrolled inflammation is associated with many diseases, trauma, and surgical interventions that may lead to sepsis and loss of life. Resolution of inflammation was held to be passive but should ideally be self-limited. We mapped and elucidated the roles of previously unknown families of resolution phase mediators collectively grouped by function as specialized pro-resolving mediators (SPM). The SPM include resolvins, protectins and maresins. In this period of support, Project 1 discovered endogenous resolution programs that are activated by infections where specific SPM are produced with potent anti-inflammatory and pro-resolving actions as well as the ability to enhance microbial clearance. Molecular understanding of resolution programs for acute infectious inflammation is critically needed to appreciate the endogenous chemical signals that help resolve innate host responses to injury and trauma. In this renewal, Project 1 focuses on functional elucidation of entirely new resolution mediators discovered in this P01. We identified novel SPM-sulfido-conjugates (SC) using unbiased mediator-lipidomics and infectious resolving exudates that possess potent actions with neutrophils (PMN), macrophage (M?) and in tissue regeneration. Given their unique structures and actions, the 3 new series of bioactive molecules are termed Maresin- Conjugates in Tissue Regeneration (MCTR), Resolvin-Conjugates in Tissue Regeneration (RCTR) and Protectin-Conjugates in Tissue Regeneration (PCTR). Our Project 1 mission is to elucidate these chemical signals and cellular pathways that activate resolution of infectious-inflammation so they can be harnessed by testing an innovative hypothesis: Namely, In acute inflammation and infection, newly elucidated members of the SPM-sulfido-conjugates (SPM-SC) are produced by resolving infectious exudates to activate resolution and tissue regeneration programs essential to reestablish tissue function. To address this, 3 specific aims are proposed: We shall determine: 1) the relationships between novel pathways and mediators within innate exudates that activate both resolution and regeneration; 2) validation and actions of novel SPM-SC, 3) determine SPM-SC activated genes in infection-tissue regeneration & resolution and, with Project 2 and Core B, demonstrate local SPM functions in humans. Results from these can impact patient care by providing rigorous evidence for new resolution mediators that control infection-inflammation and communicate in tissue regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM095467-10
Application #
9906235
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2020
Total Cost
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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Winkler, Jeremy W; Libreros, Stephania; De La Rosa, Xavier et al. (2018) Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and validation. J Leukoc Biol :
Wu, Bian; Werlin, Evan C; Chen, Mian et al. (2018) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 68:188S-200S.e4

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