CAREER: Control of NOD2-dependent Lipid Mediator Production

The University Of Central Florida Board Of Trustees, Orlando FL

Investigators

Abstract

This research aims to better understand a specific biological process, the production of lipid mediators. Lipid mediators are involved in both starting and ending inflammation, and are important for the movement of immune cells in the body, both for the regulation of body temperature, and for the detection of pain. By understanding how such mediators are produced, we might one day be able to guide the development of therapies which promote the resolution of inflammation. In the course of pursuing these research goals, this project will uncover new knowledge to advance the field, develop techniques which can be adopted by any scientist interested in conducting lipid mediator research, and to provide enriching and effective training and research experiences for both graduate and undergraduate students. This research aims to understand the molecular basis for NOD2-dependent lipid mediator production. Nucleotide-Binding Oligomerization Domain-Containing Protein 2 (NOD2) is a receptor that responds to bacterial peptidoglycan to promote the production of pro-inflammatory cytokines and antimicrobial peptides important in mediating host defense. While the intracellular signaling pathways downstream of NOD2 leading to pro-inflammatory cytokine production have been extensively studied, there is little known about the mechanisms underlying NOD2-dependent lipid mediator production. Preliminary data in the investigator's laboratory demonstrates that agonism of NOD2 leads to the production of both pro-inflammatory and pro-resolution lipid mediators. Mechanistically, the investigator finds that Receptor-Interacting Serine/threonine Protein Kinase 2 (RIP2), the kinase downstream of NOD2, can promote the modification and activation of 5-lipoxygenase (5LO), an enzyme with well-known roles in lipid mediator production. To verify the findings and elucidate the molecular mechanisms underlying NOD2-dependent lipid mediator production, the investigator proposes to: (1) Determine whether endogenous stimulation of NOD2 also results in RIP2-dependent phosphorylation and activation of 5LO; (2) Determine the molecular features of RIP2 which are important for 5LO activity and for lipid mediator production, and; (3) Develop a Group Effort in Applied Research (GEAR) course designed to engage students and provide them with a quality Undergraduate Research Experience (URE). This award is funded by the Cellular Dynamics and Function Cluster of the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.