The effects of depleted uranium shrapnel on mitochondrial cellular function, administrative diversity supplement

项目摘要 现代战争的一个后果是通过使用含铀物质而暴露于贫铀 弹药。了解环境或职业接触贫铀的影响很重要 为保护人类健康。铀化学毒理学领域的研究取得了不同的结果， 增加了贫铀暴露风险和行动机制的不确定性。家长补助金 （R15 ES032923-01，于 2024 年 4 月 30 日结束）将解决斑马鱼和 紫外线辐射可能在增强（或协同）铀的作用机制中发挥作用，通过确定 皮下颗粒或水性 DU 暴露对线粒体形态和功能的损害程度 （目标 1）如果同时暴露 DU 和 UV-B 会协同损害线粒体嵴和核 DNA（目标 2）。正在解决的核心问题是贫铀是否通过弹片或 伤口污染会导致持续的细胞和遗传损伤，包括线粒体功能障碍和 核 DNA 损伤，这两种情况都在癌症状态下观察到。 该多样性补充申请是家长补助金的延伸，通过确定以下因素的影响 贫铀对线粒体 DNA 的影响，而 Parent Grant 则研究贫铀对核的影响 基因组和线粒体生理学。我们将解决首要问题，如果线粒体基因组 是贫铀化学毒性的目标。我们假设细胞中的贫铀可以 损害线粒体DNA，导致线粒体功能下降。我们将通过以下方式检验我们的假设 扩展具体目标 1 和 2 以包括补充具体目标 (SSA) 1b 确定是否接触 DU 皮下 DU 颗粒暴露或水性 DU 暴露会损害线粒体 DNA；和SSA.2b 确定同时暴露于 DU 和 UV-B 是否会协同损害线粒体 DNA。 除了该项目涵盖的关键生物医学科学之外，家长的总体目标 R15 是让学生参与拟议研究活动的各个方面。推而广之，多样性 家长补助金的补助金将为二年级博士生 Phillip Kalaniopio 先生和 夏威夷原住民，开展上述研究作为其论文研究的主要组成部分。 经验丰富的导师团队将通过每周一次的面对面会议来指导卡拉尼奥皮奥先生讨论研究 设计和分析，此外还有他的首席导师（Matthew Salanga 博士）在实验室进行的实践培训。 对科学写作（例如手稿、资助提案）的指导支持将来自每月的会议和 与美洲原住民癌症预防计划的主要研究人员举办研讨会： Drs.贾尼·英格拉姆 （北亚利桑那大学，NIH U54CA143925）和 Ronald Heimark（亚利桑那大学；NIH） U54CA143924）。本补充材料的一个目标是 Kalaniopio 先生在第二年上半年提交 F31。

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 supplement is submission of an F31 by Mr. Kalaniopio in the first half of Yr2.