Targeting microRNAs to modulate neutrophil trafficking and improve resolution of gut inflammation.

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

Neutrophil activity in tissues can exacerbate inflammation and promote tissue damage, as seen in inflammatory bowel diseases (IBD). Thus, studies focused on PMN trafficking are of continued interest and physiological significance. Crossing of the endothelial cell (EC) barrier is the first critical regulatory step in tissue PMN effector function and targeting existing and novel signaling molecules/pathways involved in this process is an attractive therapeutic strategy. miRNAs-focused therapies are an exciting emerging field, with several miRNA therapeutics already approved for clinical use and more being tested in clinical trials. Identification of miRNAs has been acknowledged by the 2024 Nobel Prize in Medicine, highlighting their significant impact and potential as therapeutics. As such miRNAs present an exciting opportunity for therapies, as their expression can be easily manipulated using synthetic miRNA mimics or antagonists, which can be synthesized as cell permeable molecules with superior tissue uptake. miRNAs broadly regulate many biological processes and have been implicated in IBD pathogenesis and heightened immune response. Specifically, miRNAs can regulate organization of the actin cytoskeleton, cell polarity, cytokine/chemokine signaling and cell adhesion, all of which are critical regulatory process of neutrophil transendothelial migration (TEM).Thus, in the current studies we propose to perform an unbiased miRNA profiling in circulating PMNs in clinically relevant infectious, salmonella- induced and DSS-induced colitis/injury models followed by phenotypical and functional target validation with the goal of 1. Identifying novel microRNAs that regulate PMN TEM in gut inflammation and 2. Establishing whether manipulating miRNA activity can effectively suppress PMN TEM and improve resolution of gut inflammation. In preliminary work we established the premise for targeting reduction in neutrophil migration and tissue accumulation to improve disease outcomes in these models. We also optimized all relevant protocols for blood neutrophil isolation and mRNA sequencing. These high-risk-high-reward studies are well suited for the R21 funding mechanism as they provide a platform for the development of novel interventions, such as miRNA therapeutics, aimed at regulation of PMN crossing of the vascular wall and trafficking into tissue, which will help achieve important clinical endpoints, including resolution of mucosal inflammation and wound healing.