PROJECT ABSTRACT A consequence of modern combat is exposure to depleted uranium through the use of uranium-containing munitions. Understanding the effects of environmental or occupational exposure to depleted uranium is important for protecting human health. Research in the area of uranium chemical toxicology has yielded mixed results, raising uncertainty as to the risks of depleted uranium exposure and mechanisms of action. The Parent Grant (R15 ES032923-01, ending 04/30/2024) will address depleted uranium chemical toxicity in zebrafish and the role ultraviolet radiation may play in potentiating (or synergizing) uranium’s mechanisms of action, by determining the extent to which subcutaneous particles or waterborne DU exposure impairs mitochondrial form and function (Aim 1) and if concomitant exposure of DU and UV-B synergistically damages mitochondrial cristae and nuclear DNA (Aim 2). The central question being addressed is if depleted uranium internalized through shrapnel or wound contamination causes persistent cellular and genetic damage including mitochondrial dysfunction and nuclear DNA damage, both of which are observed in cancer states. This Diversity Supplement Application is an extension of the Parent Grant by determining the impacts of depleted uranium on mitochondrial DNA, whereas the Parent Grant investigates DU effects on the nuclear genome and mitochondrial physiology. We will address the overarching question, if the mitochondrial genome is a target of depleted uranium chemical toxicity. We hypothesize that depleted uranium in a cell can damage mitochondrial DNA resulting in reduced mitochondrial function. We will test our hypothesis by expanding Specific Aims 1 and 2 to include Supplemental Specific Aim (SSA) 1b Determine if exposure to DU from subcutaneous DU particle exposure or waterborne DU exposure damages mitochondrial DNA; and SSA.2b Determine if concomitant exposure to DU and UV-B synergistically damages mitochondrial DNA. In addition to the critical biomedical science encompassed by this project, an overarching goal of the Parent R15 is to involve students with all aspects of the proposed research activities. By extension, a Diversity Supplement under the Parent Grant will provide support for Mr. Phillip Kalaniopio, a 2nd year PhD student and Native Hawaiian, to carry out the studies described above as the primary component of his dissertation research. An experienced mentorship team will guide Mr. Kalaniopio via weekly in-person meetings to discuss research design and analysis, in addition to hands on training in the laboratory with his lead mentor (Dr. Matthew Salanga). Mentoring support for scientific writing (e.g., manuscripts, grant proposals) will come from monthly meetings and workshops with the Native American Cancer Prevention Program’s Principal Investigators: Drs. Jani Ingram (Northern Arizona University, NIH U54CA143925) and Ronald Heimark (University of Arizona; NIH U54CA143924). One goal for this suppleme...