Novel Strategies for Tackling Inflammatory Respiratory Diseases based on the Exploitation of the Proresolving Receptor FPR2/ALX

The specific goal of the proposed research is providing new therapeutic strategies to tackle and reduce the burden of inflammatory respiratory diseases (RD), which are among the leading cause of disability and mortality. The paradigm currently employed in the treatment of inflammatory RD is to inhibit components of inflammatory response (e.g., with non-steroidal anti-inflammatory drugs, corticosteroids, or anti-cytokine biological drugs). However, these therapies are only effective in limiting the symptoms, but do not cure the disease and have many side effects. Thus, there is an urgent need for novel therapeutics and approaches in the treatment of inflammatory RD. Accruing evidence from the PI’s previous research and work in progress signifies that harnessing the body’s anti-inflammatory, proresolving, and tissue protective pathways driven by the FRP2/ALX receptor is a viable and innovative therapeutic strategy in treating inflammatory disease. Therefore, a multipronged, highly translational, and innovative research program is assembled with 2 specific aims among 2 research units: 1. To generate synthetic FPR2 peptide ligands and test their pharmacological properties and actions in RD 2. To obtain novel inhalable drug formulations suitable for local delivery of FPR2 ligands In workpackages (WP) 1 different FPR2 ligands will be synthesized. WP2 will focus on determining their in vitro/in vivo bioactions using advanced technologies (LC-MS, RNASeq), and pharmacokinetics and on producing and characterizing GMP-grade, Eu-Pharmacopiea compliant, inhalable formulations. WP3 will focus on project coordination and dissemination activities, which are key for maximizing the scientific, societal, economical, and technological impact of the project. Through the systematic and timely accomplishment of these aims, the proposed research will 1. Contribute to the progress in our knowledge of severe acute and chronic inflammatory RD and importance of FPR2-driven endogenous pro-resolution pathways in RD 2. Go beyond the state of the art of therapeutic approaches to RD providing new strategies to tackle RD and reduce their health, social, and economical burden Although our proposal is a high risk/high gain project, it will maximize the MUR PNRR-based research, capitalizing on the significant innovation This ambitious objective can only be achieved through a multidisciplinary and multi-sectorial approach with expertise from distinct research fields synergizing to push the boundaries of our understanding of fundamental tissue protective mechanisms towards a new frontier of resolution pharmacology. Given that these molecules will exploit the body’s own protective programs they are anticipated to be more effective in treating disease then current therapeutics and carry a lower burden of side effects.