The overall objective of our Phase I Center of Biological Research Excellence (COBRE) is to establish the Nevada COBRE in Molecular and Cellular Signal Transduction in the Cardiovascular System at the University of Nevada, Reno (UNR) and the UNR School of Medicine (UNR Med) as a sustainable, thematic, interdisciplinary basic science research Center. This mission will be accomplished by developing and utilizing state-of-the-art molecular, genetic, biophysical, and biomedical imaging technologies. The COBRE comprises an Administration Core (Core A) headed by the Program Director, Dr. Scott Earley, two Research Cores, and 5 Project Leaders. Dr. Yumei Feng Earley is the Director of the Transgenic Animal Genotyping and Phenotyping Core (Core B) and Dr. Normand Leblanc directs the High Spatial and Temporal Resolution Imaging Core (HSTRI; Core C), which provides the Project Leaders with access to a wide array of state-of-the-art instruments enabling high spatial and temporal resolution imaging of cells and tissues samples labeled with fluorescent indicators. The COBRE is submitting an application for an Administrative Supplement in response to NOSI NOT-GM-21- 029 that will enhance the capabilities of the HSTRI Core. The Specific Aim of this application is to purchase a new Leica STELLARIS SP5 Laser Scanning Confocal Microscope to replace an old Olympus FV1000 Laser Scanning Confocal Microscope. The price tag for this new system is $316,286.70. If NIGMS provides $250,000, the remaining $66,286.70 will be provided through institutional support. The FV1000 system, which is the most utilized microscope by COBRE Project Leaders and other UNR investigators served by the HSTRI Core, was purchased in 2010. Unfortunately, the microscope has recently become unreliable with 51 out of 120 days of down time (42.5%) in 2021 alone and has thus reached the limit of its usable life. These repetitive failures have negatively impacted the research productivity of the Center, a situation that will require a more permanent solution in the future. The Leica STELLARIS SP5 system dramatically increases the temporal and spatial resolution relative to the Olympus FV1000, which are key features for several investigators in our Center (all 5 COBRE Project Leaders), including the research programs of more established members of the Center, and other UNR biomedical investigators. As configured, the microscope has Adaptive Focus Control with 20 nm repositioning accuracy, which the FV1000 lacks, and can perform FRET, FRAP, and FLIP experiments, and could be easily upgraded to perform super-resolution microscopy. Thus, the Leica STELLARIS SP5 system will replace and advance the capabilities of the FV1000.