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.