Project Abstract Funding is requested to acquire a state-of-the-art mass spectrometer for MALDI Imaging Mass Spectrometry (MALDI IMS) in support of multiple NIH-funded programs at UC Irvine. The instrument is based on a AP-MALDI-QTOF design optimized for imaging by high-speed, high resolution acquisition of mass spectra from raster laser scanning of matrix-coated 2D specimens. MALDI IMS provides a proven technique capability of retaining spatial information alongside high dimensional ion mass detection. Supported projects originate from researchers in the Schools of Physical Sciences, Biological Sciences, Engineering, Medicine and Pharmacy & Pharmaceutical Sciences. The instrument will, therefore, be truly a shared inter-disciplinary resource. Projects of the major users include, 1) neuropathological proteins and lipid phenotyping in Alzheimer’s disease models, 2) investigating metabolic heterogeneity in tumors, 3) evalauting ECM composition of engineered cartilage, 4) defining age/environmental changes of lens cyrstallins, 5) spatial plant metabolomics and 5) assessing lipid/protein distributions in dry eye syndrome. All the projects are pursuant of highly defined goals where the spatial organization of biomolecules (metabolites, lipids, peptides/proteins) is a critical component for understanding the molecular organization and function or dysfunction of tissues. For optimal access, maintenance and expert operational support, the instrument will be placed in UCI’s Mass Spectrometry Core Facility. UCI has long supported the MSF with permanent funding for full-time facility staff members: a PhD-level director with >30 years experience as a multidisciplinary research scientist, complemented by a proteomics specialist with expertise in MALDI and LC-MS techniques, and an instrument operator. Normal facility operational funds are obtained though a well established stable recharge system. Additional extended service support is provided through pledged institutional funds. All 20 instruments in the Facility are intensively used, particularly for small molecule analysis, top down proteomics and metabolomics with most available 24/7 as walk-up open access instruments. In fiscal year 2021-2022 the facility analyzed >35K samples by 300 users, with many users receiving advanced instrument training. The MALDI-IMS instrument will be run as a staff-operated service but also made accessible to qualified trained users to maintain a high sample throughput and maximum use. The research outlined in the proposal highlights an urgent need for an advanced but user-friendly instrument that is not currently available at UCI; a fast MALDI-QTOF IMS system for high quality biomolecular spatial phenotyping.