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，通过使用含铀弹药， 军火了解环境或职业接触贫铀的影响很重要 保护人类健康。铀化学毒理学领域的研究结果好坏参半， 这增加了贫铀接触风险和作用机制的不确定性。家长补助金 (R15 ES 032923 -01，2024年4月30日结束）将讨论贫化铀对斑马鱼的化学毒性， 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 皮下颗粒或水溶性贫铀暴露损害线粒体形式和功能的程度 (Aim 1）如果同时暴露于DU和UV-B协同损害线粒体嵴和核 DNA（目标2）。正在处理的中心问题是，贫铀是否通过弹片或 伤口污染引起持续的细胞和遗传损伤，包括线粒体功能障碍， 核DNA损伤，这两种损伤都在癌症状态中观察到。 本多样性补充申请是母公司补助金的延伸，通过确定 贫铀对线粒体DNA的影响，而母基金则研究贫铀对细胞核的影响。 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 损伤线粒体DNA，导致线粒体功能降低。我们将测试我们的假设， 扩大具体目标1和2，以包括补充具体目标1b 皮下贫铀颗粒暴露或水溶性贫铀暴露损害线粒体DNA;和SSA.2b 确定同时暴露于DU和UV-B是否协同损伤线粒体DNA。 除了该项目所涵盖的关键生物医学科学外， R15是让学生参与拟议研究活动的各个方面。通过扩展，多样性 家长补助金下的补充将为菲利普Kalaniopio先生提供支持，他是一名二年级的博士生， 夏威夷本地人，进行上述研究作为他的论文研究的主要组成部分。 一个经验丰富的导师团队将通过每周面对面的会议指导Kalaniopio先生讨论研究 设计和分析，除了在实验室与他的首席导师（马修·萨朗加博士）动手培训。 对科学写作的指导支持（例如，手稿，赠款提案）将来自每月会议， 与美洲原住民癌症预防计划的主要研究者：贾尼英格拉姆博士的研讨会 （北方亚利桑那大学，NIH U 54 CA 143925）和罗纳德海马克（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.