The effects of depleted uranium shrapnel on mitochondrial cellular function.

贫铀弹片对线粒体细胞功能的影响。

• 批准号: 10201131
• 负责人: Matthew Salanga
• 金额: $ 42.73万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-21 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201131
• 关键词: Acute; Address; Adult; Affect; Afghanistan; Animals; Area; Award; Beta Particle; Biological; Cell Culture Techniques; Cell physiology; Chemicals; Chronic; Crista ampullaris; Cutaneous; DNA; DNA Damage; Data; Embryo; Environmental Exposure; Exposure to; Face; Fishes; Genetic; Genome Stability; Goals; Health; Home; Human; Impairment; Implant; Ingestion; Inhalation; Injury; Iraq; Isotopes; Laboratories; Larva; Longitudinal Studies; Malignant Neoplasms; Metabolism; Metals; Methods; Military Personnel; Mitochondria; Mitochondrial DNA; Modernization; Native Americans; Native-Born; Navajo; Nuclear; Nuclear Weapon; Occupational; Occupational Exposure; Organism; Outcome; Persons; Physiological; Pigments; Play; Population; Production; Radiation; Radioactivity; Radioisotopes; Reactive Oxygen Species; Relaxation; Research; Research Activity; Research Personnel; Risk; Rodent Model; Role; Route; STEM career; Science; Side; Site; Skin; Soil; Soldier; Students; Sun Exposure; System; Techniques; Testing; Time; Toxic effect; Toxicology; Tribes; UV Radiation Exposure; Ultraviolet Rays; Uncertainty; Underrepresented Populations; United States; Uranium; Veterans; War; Zebrafish; base; cell injury; combat; contaminated water; cost; experimental study; exposed human population; genotoxicity; graduate student; improved; in vivo; innovation; insight; irradiation; mitochondrial dysfunction; multilevel analysis; next generation; novel; particle; photoactivation; response; subcutaneous; ultraviolet; undergraduate student; waterborne; weapons; wound

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 research proposed here will address depleted uranium chemical toxicity in vivo and the role ultraviolet radiation may play in potentiating (or synergizing) uranium’s mechanisms of action. 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 DNA damage, both of which are observed in cancer states. In addition to the critical biomedical science encompassed by this project, an overarching goal of R15 awards is to involve students with all aspects of the proposed research activities to engage the next generation of STEM investigators. Students will carry out experiments using zebrafish (embryos, larvae and adults), to test the hypothesis that internalized depleted uranium, in amounts that are occupationally and environmentally-relevant, disrupts mitochondrial function and genomic stability. We will also test the hypothesis that ultraviolet B-ray (UV- B) radiation interact with DU leading to synergistically increased genotoxicity. Notably, humans exposed to depleted uranium, particularly as a consequence of shrapnel, may carry the metal burden in or near their skin where interaction with sun exposure (including UV-B) may occur. Our studies leverage a pigment-free strain of zebrafish that enables longitudinal tracking of uranium implants, as the animal’s skin is transparent as a larva and translucent as an adult. Our unique study system is tractable for students as demonstrated by our preliminary data in which the great majority of data was produced by student researchers in the PI’s laboratory group. Furthermore, the zebrafish is less costly than rodent models and relatively easy to maintain, making longitudinal studies well within our capabilities. Outcomes derived from these studies will provide evidence for or against uranium chemical toxicology from acute or persistent exposure from multiple routes of internalization. We assert this is a comprehensive approach to assess the risk depleted uranium poses to humans while addressing potential risk modifiers.

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 了解环境或职业接触贫铀的影响非常重要。 为了保护人类健康，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。 这里提出的将解决贫铀在体内的化学毒性以及紫外线辐射可能发挥的作用 增强（或协同）铀的作用机制所要解决的核心问题是。 通过弹片或伤口污染内化的贫铀会导致持久的细胞和遗传 包括线粒体功能障碍和 DNA 损伤，这两者都在癌症状态下观察到。 除了该项目涵盖的关键生物医学科学之外，R15 奖项的总体目标 让学生参与拟议研究活动的各个方面，以参与下一代 STEM 研究人员将使用斑马鱼（胚胎、幼虫和成体）进行实验，以测试 假设内化贫铀的数量与职业和环境相关， 我们还将测试紫外线 B 射线 (UV-) 的假设。 B) 辐射与 DU 相互作用，导致遗传毒性协同增加。值得注意的是，暴露于 DU 的人类。 贫铀，特别是弹片造成的贫铀，可能会将金属负担带入或靠近皮肤 可能会与阳光照射（包括 UV-B）发生相互作用。 我们的杠杆作用研究了一种无色素的斑马鱼品种，它能够纵向跟踪铀植入物， 因为动物的皮肤在幼虫时是透明的，在成年时是半透明的，我们独特的研究系统很容易处理。 正如我们的初步数据所示，其中绝大多数数据是由学生产生的 此外，斑马鱼的成本低于啮齿动物模型和 相对容易维护，使纵向研究完全在我们的能力范围内。 这些研究的结果将为支持或反对铀化学毒理学提供证据 我们断言这是一种综合方法。 评估贫铀对人类造成的风险，同时解决潜在的风险调节因素。