Macrophages are increasingly recognized as key regulators of common diseases such as neurodegeneration, cancer and liver disease. Central to macrophage functionality is their ability to attain different activation states, ranging from inflammation-inducing to inflammation-resolving and healing states. The precise phenotype and functions adopted are

highly context dependent and have been shown to be driven by the local microenvironment in which the macrophages reside. Emerging evidence indicates that many pathological conditions are associated with alterations in macrophage phenotypes/functions due to a shift in their activation state, however whether this is a result of true macrophage

plasticity or the recruitment of a phenotypically distinct macrophage population is also disease-specific. Crucially, recent studies have demonstrated a role for lipids and altered lipid metabolism in regulating the phenotypes and functions of disease-associated macrophages. In this project, we bring together unique complementary expertise from both academia and industry to design strategies for the functional reprogramming of macrophages by interfering with lipid metabolism. To

this end, and instructed by the real-world needs of the industrial partners, we will set up a comprehensive technology pipeline involving state-of-the-art lipidomics approaches to map the heterogeneous landscape of macrophage phenotypes in terms of lipid metabolism in healthy and diseased tissue. Using gold-standard preclinical models, we will identify and validate key enzymes in lipid metabolism as potential targets and will provide proof of concept of pharmacological and/or

nutraceutical approaches to regulate macrophage functions. This pipeline can be used for unbiased discovery but also offers multiple entry points to validate predefined targets in a hypothesis-driven manner.