Project Summary/Abstract The proposal is to request support for the purchase of the 200 kV Glacios Transmission Electron Cryo- microscope from Thermo Fisher Scientific Inc.. The requested instrument will replace our current Tecnai G2 Polara (300 kV) cryomicroscope, which was purchased nearly two decades ago and is currently at the end of its usefulness. At this time, Thermo Fisher does not provide service contract for the Polara and to keep the microscope operational is becoming a challenge that jeopardizes our investigators and their NIH funded projects. Strong institutional support is provided with a cost-sharing commitment of $1,000,000 to the purchase of the proposed Glacios and another ~$1,000,000 for over five years to support the projected operational costs of the new cryo-TEM. The requested instrument will be integrated within the Cryo-EM Core Facility established under the umbrella of the Structural Biology Imaging Center at McGovern Medical School at the University of Texas Health Science Center (UTHealth) at Houston. UTHealth’s Cryo-EM Core Facility is a well administered, highly collaborative and user focused cryo-EM resource currently equipped with a Tecnai G2 Polara and a Titan Krios G3. A Glacios is a new generation microscope offered by Thermo Fisher that will replace our obsolete Polara while at the same time offering significant technological improvements and enabling new capabilities for our users. That includes high-throughput specimen optimization and screening through the integrated EPU software, which can be followed by contamination-free sample transfer to the Titan Krios for high-resolution imaging; optimized cryo-EM imaging using the latest generation of electron counting detector Falcon 4 integrated with the new Selectris energy filter, designed for stability and ease-of-use. The proposed Glacios will serve the needs of over two dozen research projects in key areas such as cancer, neuroscience, infectious diseases, drug discovery, antibacterial drug resistance, cell membrane transport, and others. It will deeply impact the research in the Texas Medical Center and surrounding institutions by: increasing scientific productivity; fostering interactions and collaborations amongst scientists, strengthening the competitiveness for research funding, and boosting our ability to attract new investigators and students by the prospect of using start-of-the-art cryo-EM equipment.