Chemoproteomics and Lipidomics for Identifying Dysregulated Enzymes and Lipids in Cutaneous Disorders.

PROJECT SUMMARY This project aims to advance the treatment of atopic dermatitis (AD) by identifying novel drug targets through an innovative chemical biology platform, Profiling of Active Cutaneous Enzymes (PACE), in conjunction with untargeted lipidomics. AD is characterized by skin barrier dysfunction and chronic inflammation, with lipids playing a central role in maintaining skin structure and modulating immune responses. Despite their importance, the role of lipids and lipid-regulating enzymes in AD and other skin diseases is often underappreciated due to the limitations of traditional methods for analyzing proteins and enzymes in the skin. The primary objective of this proposal is to overcome these challenges by developing the PACE platform to investigate enzyme regulation and lipid metabolism in AD. The study will begin with the identification of dysregulated enzymes and lipid alterations in human AD skin using activity-based protein profiling (ABPP) and lipidomics. These candidate enzymes will then undergo functional validation in preclinical AD models, where their expression will be modulated to assess their impact on lipid profiles, biochemical markers, and histological and clinical outcomes. Finally, the project will screen for selective inhibitors targeting these functionally validated enzymes, with the goal of developing new therapeutic strategies for AD. The expected outcomes include an enhanced understanding of the role of lipids and enzymes in skin health and disease, the identification of novel therapeutic targets, and the potential for applying this platform to other cutaneous diseases. This research aligns with the broader goals of improving treatments for skin conditions by addressing the underlying biochemical mechanisms.