Given that: 1) bioactive lipids are key pathoph...given that: 1) bioactive lipids are key pathophysiological mediators of several intracellular cellular processes, 2) altered brain lipid levels are discussed as contributing factors for neuroinflammation and 3) a role of histone acetylation in inflammation and immunometabolism has been shown; this project proposes the use of inhibitors that interfere at different points in lipid metabolism and histone acetylation mechanisms to interrogate which factors correlate to each other, either positively or negatively in neuroinflammation. the aim of this project is to combine mass spectrometry-based technologies further interrogating inflammatory-dependent changes in glial cells lipid patterns in order to understand the crosstalk between histone acetylation and bioactive lipids. specifically, this study will attempt to answer the following questions: 1) activated human ipsc-derived microglia resemble alterations in bioactive lipids, as well as in the whole-cell lipid pattern, as observed in activated murine microglia? 2) the increase in lysophosphatydilcholines (lpcs) and ceramides levels are dependent on the activity of metabolic enzymes (such as cpla2 and smases) as a result of the activation of lps/tlr4 signaling pathway in microglia? 3) if so, the hdac/bet inhibitors anti-inflammatory effects are a result of the regulation of such lipid metabolism enzyme’s activity? 4) in addition, aside from microglia, astrocytes also contribute a key role in brain immune response, thus, are these observations microglia-dependent or may involve other glial cells? the application of a combined ms-based cell fingerprinting platform in a non-targeted approach in this project will also allow an exploratory investigation into stimulus-dependent metabolic changes and their modulation by pharmacological inhibitors not restricting the analysis to a single molecule but interrogating a group of molecules, as in the case of lpcs and ceramides. further understanding of this complex crosslinked network might help to determine the biochemical pathways that are altered in disease and shed light on novel treatment approaches for cns inflammation and neurodegeneration.