PROJECT SUMMARY / ABSTRACT High content microscopy assays allow to simultaneously visualize and quantify many features in complex biological systems. Over the past years, high content microscopy-based screening has been increasingly recognized as an integral approach for identifying and characterizing novel therapeutic targets in the cellular context. The technology has also been widely adopted by pharmaceutical companies and academic screening cores for probe and drug discovery via phenotypic screening. Here, Yale Center for Molecular Discovery (YCMD) requests funds to purchase state-of-the-art ImageXpress Micro high content screening system integrated with a robotic platform to replace an outdated system which manufacturer discontinued. The requested system would meet the needs of current projects and offer major additional acquisition and analysis capabilities that are not currently accessible, ultimately expanding the scope and increasing the throughput of many biomedical research programs. YCMD (The Center) is a core facility uniquely suited for hosting and maintaining the instrument and for providing high content screening services. The Center specializes in high-throughput assay development, provides a diverse collection of small molecules and genetic libraries, and maintains a sophisticated infrastructure, including cutting-edge instrumentation and analysis databases, to support screening. Staffed with a highly experienced team and supported by the university, the Center serves a diverse and broad user base, annually supporting projects from over 40 different laboratories from various departments across Yale and non-Yale institutions. Notably, the core supports at least ten major high- throughput microscopy-based projects each year and has a strong track record of successfully executing image-based projects for translational biomedical programs. This application is supported by nine faculty members identified as major instrument users, and two minor users, encompassing seven different Yale departments and an external institution. Their innovative programs span a wide range of basic, translational, and clinical research areas and address many therapeutic indications including cancer, heart diseases, developmental and neurological disorders, and skin diseases. Majority of the users have NIH funding, and their translational research is also supported by the Department of Defense and private and institutional funds. High content screening system is critical to support high-throughput research of the users, and ImageXpress Micro system requested in this application would represent a major opportunity to implement and advance current and future transformative biomedical programs which have direct implications for human health.