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

项目摘要 现代战斗的一个后果是通过使用含铀的武器暴露在贫铀中。 军需品。了解环境或职业暴露于贫铀的影响很重要。 为了保护人类健康。铀化学毒理学领域的研究结果喜忧参半， 增加了贫铀暴露的风险和行动机制的不确定性。《家长格兰特》 (R15 ES032923-01，截至2024年4月30日)将讨论斑马鱼和 紫外线辐射在增强(或协同)铀的作用机制中可能发挥的作用，通过确定 皮下微粒或水性贫铀暴露对线粒体形态和功能的损害程度 (目标1)如果同时暴露于DU和UV-B，则协同损伤线粒体脊和核 DNA(目标2)。正在解决的中心问题是贫化铀是通过弹片内化还是 伤口污染会导致持续性的细胞和遗传损伤，包括线粒体功能障碍和 核DNA损伤，这两种损伤都在癌症状态下观察到。 这项多样性补充申请是父母补助金的扩展，通过确定以下影响 贫铀对线粒体DNA的影响，而母公司Grant研究DU对核的影响 基因组和线粒体生理学。我们将解决最重要的问题，如果线粒体基因组 是贫铀化学毒性的目标。我们假设一个细胞中的贫铀可以 损伤线粒体DNA，导致线粒体功能降低。我们将通过以下方式验证我们的假设 扩展特定目标1和2以包括补充特定目标(SSA)1b确定是否接触DU 皮下DU颗粒暴露或水中DU暴露会损伤线粒体DNA；以及SSA.2b 确定同时暴露在DU和UV-B下是否会协同损伤线粒体DNA。 除了这个项目包含的关键生物医学科学之外，父母的一个首要目标 R15是让学生参与所提议的研究活动的所有方面。推而广之，多样性 家长补助金项下的补助金将为Phillip Kalaniopio先生提供支持，Phillip Kalaniopio先生是一名二年级博士生， 夏威夷原住民，将上述研究作为其学位论文研究的主要组成部分。 一个经验丰富的指导团队将通过每周面对面的会议指导卡拉尼奥皮奥先生讨论研究 除了与他的首席导师(马修·萨兰加博士)一起在实验室进行动手培训外，还需要进行设计和分析。 对科学写作(例如，手稿、拨款提案)的指导支持将来自每月会议和 与美洲原住民癌症预防计划主要研究人员的研讨会：Jani Ingram博士 (北亚利桑那大学，NIH U54CA143925)和Ronald Heimark(亚利桑那大学；NIH U54CA143924)。本增刊的目标之一是卡拉尼奥皮奥先生在第二年上半年提交一辆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.