Mechanisms of inflammation resolution by Specialized Pro-resolving Mediators

Objetivo

Inflammation is an immunovascular process occurring upon pathogen infection and pathological conditions. Strong evidence from the last two decades shows that termination of inflammation is not a passive process but instead, is actively terminated. Such Inflammation Resolution (IR) stops tissue damaging processes while enhancing immune response and tissue repair. Enhancing IR has the potential to improve treatments in chronic inflammation, autoimmune diseases, atherosclerosis, neurodegeneration and cancer. Specialized Pro-resolving Mediators (SPMs) are lipid-derived molecules with a pivotal role in inducing IR and act through putative orphan G protein-coupled receptors (GPCRs) on the surface of immune cells (some acting through unknown receptors). Despite the high relevance of SPMs in IR and the treatment of inflammation-related diseases, there is scarce knowledge in their functional mechanisms, as well as in their relative and absolute effect.

In the ReSolVer proposal we will use chemical synthesis, chemoproteomics, signaling, structural biology and primary 3D epithelioids to understand SPM mechanisms and provide a cell/tissue/disease inspecific SPM-receptor network so as to tackle the pleitropic effects of SPMs in different organs/disease. More specifically, we will:

(i) Identify, validate and de-orphanize SPM receptors, using chemoproteomics, in vitro binding and signaling assays,
(ii) Generate a functional SPM-receptor network, of SPM-receptor interactions, signaling profiles and cell expression levels,
(iii) Determine the structural mechanisms of SPM-receptor interactions, using cryo-EM of SPM-receptor complexes and functional assays,
(iv) Design and test synergistic SPM therapeutic strategies, based on the generated SPM-receptor network and human 3D primary epithelioids,

The results will provide a breakthrough in inflammation resolution, tackle GPCR de-orphanization and open new therapeutic avenues in inflammation-related diseases.