Project 3: Elemental Microscopy for Detection of Radionuclide Distribution and Development of Cell and Tissue Phantoms

项目 3：用于检测放射性核素分布和细胞和组织模型开发的元素显微镜

• 批准号: 10327398
• 负责人: GAYLE E. WOLOSCHAK
• 金额: $ 37.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327398
• 关键词: 3-Dimensional; Acute; Address; Affect; Animal Model; Animals; Archives; Back; Biological; Biological Markers; Canis familiaris; Cell Death; Cell Lineage; Cells; Chemicals; Chemistry; Complex; DNA Damage; Data; Daughter; Deposition; Detection; Development; Devices; Dimensions; Discipline of Nuclear Medicine; Distant; Elements; Evaluation; Exposure to; External Beam Radiation Therapy; Fibrosis; Fluorescence; Fluorescence Microscopy; Generations; Genetic Transcription; Genotype; Goals; Half-Life; Health; Heterogeneity; Histologic; Histology; Image; Immune; Immune system; Immunohistochemistry; Immunology; Infiltration; Inhalation; Intake; Left; Life; Link; Liver; Location; Lung; Lymphocyte; Lymphoid Cell; Maps; Messenger RNA; MicroRNAs; Microscopy; Modeling; Molecular; Molecular and Cellular Biology; Morphology; Motivation; Mus; Myeloid Cells; Nature; Normal tissue morphology; Nuclear; Nuclear Reactor Accidents; Organ; Organism; Outcome; Particle Size; Particulate; Pattern; Periodicity; Phenotype; Positioning Attribute; Production; Property; Radiation; Radiation Protection; Radiation induced damage; Radiobiology; Radioisotopes; Radiology Specialty; Recovery; Research; Resources; Roentgen Rays; Route; Sampling; Selection Criteria; Signal Transduction; Slide; Solubility; Source; Spleen; Technology; Time; Tissue Sample; Tissues; Tomogram; Toxic effect; Universities; Vertebral column; Visible Radiation; animal tissue; biomarker discovery; biomarker evaluation; cell injury; chemokine; cytokine; density; dosimetry; efficacy evaluation; grasp; improved; in vivo; insight; internal radiation; intravenous injection; light microscopy; macrophage; microscopic imaging; morphometry; nanoscale; radiation mitigation; radiochemical; response; sample archive; senescence; stem; submicron; synergism; tissue archive; tissue phantom; tool

PROJECT 3: ABSTRACT The overall objective of Project 3 is to link radionuclide exposure and the elemental signature left behind with biomarkers of that exposure, be they histological, cellular or molecular in nature. Our motivation to do this stems from the fact that radiation from internal emitters is very unevenly distributed in organs, tissues, and cells and the fact that this remains little understood. Heterogeneity of radionuclide distribution is dependent upon a complex set of parameters that relate to the radionuclide itself and the organism’s response to it, such as radionuclide half-life, decay schema, activity, concentration, particle size, morphology, chemical form, and solubility, whereas the biological response patterns are dictated by the genotype and phenotype of the cells, tissues and organs, intake route and the organism as a whole. Because the in vivo footprint of radionuclide exposure is multi-scale, e.g., DNA damage and cell death at the (sub)cellular level, or chemokine/cytokine production at the cell/tissue level, it essentially means that biomarkers of that exposure are best registered along the same multi-dimensional NANO-, MICRO- and MESO scale, which is our goal. For example, micro-RNA expression will be registered in the context of immune cell infiltration in a tissue, particularly macrophages. Arguably, the most compelling aspect to our project can be seen in the use of X-ray fluorescent microscopy (XFM) as a powerful tool for radionuclide mapping, which forms the backbone to our approach. Applying XFM technology to explore the incredibly rich resource that the Northwestern University Radiation Animal (NURA) Archive, combined with contemporary animal models gives us the unique opportunity to trace back the biological consequences of radionuclide exposures, and opens up the path towards biomarker, and ultimately, to mitigator discovery. Canine and murine tissues from an enormous number of animals exposed to a variety of radionuclides and over different times add critical mass and rigor to our study. Collectively, our team can draw from a diverse set of expertise in nuclear medicine, cellular and molecular biology, radiobiology, XFM, radiation protection and mitigation, normal tissue radiobiology and immunology. We are ideally placed to carry out the proposed studies addressing the complexity of radionuclide exposure in a comprehensive and integrated way. Our hope is to gain important insights into the biological consequences of internal radiation emitters that are relevant to real life accidental and incidental exposure scenarios and that cannot be modeled using conventional external beam radiation or nuclear medicine approaches. Yet, the concepts underlying the interaction between radiation-damaged cells and tissues, danger signaling, the engagement of immune system and the road to recovery are likely applicable in a much broader context.

项目3：摘要 项目3的总体目的是将radiuclide的暴露和留下的元素签名联系起来 这种暴露的生物标志物，无论是组织学，细胞还是分子本质上。我们进行这一阶段的动力 从内部发射器的辐射的事实非常不均匀地分布在器官，组织和细胞中， 这仍然很少理解。放射性分布的异质性取决于 与放射线本身以及生物体对其的反应有关的复杂参数集，例如 放射性半衰期，衰减模式，活性，浓度，粒度，形态，化学形式和 溶解度，而生物学反应模式由细胞的基因型和表型决定，， 组织和器官，摄入途径和整个生物。 因为放射性辐射的体内足迹是多尺度的，例如DNA损伤和细胞死亡 （子）细胞水平或细胞/组织水平的趋化因子/细胞因子的产生，这实际上意味着生物标志物 该暴露量最好沿着相同的多维纳米，微观和中索量表进行注册，其中 是我们的目标。例如，微-RNA表达将在A中的免疫细胞浸润的背景下进行注册 组织，尤其是巨噬细胞。可以说，我们项目最引人注目的方面可以看到 X射线荧光显微镜（XFM）作为放射性映射的强大工具，形成了骨干 我们的方法。应用XFM技术探索西北大学的令人难以置信的丰富资源 辐射动物（NURA）档案，结合现代动物模型为我们提供了独特的机会 追溯辐射液暴露的生物学后果，并打开通往生物标志物的路径， 并最终要进行缓解剂发现。来自大量动物暴露的犬和鼠组织 到各种放射线，在不同的时间为我们的研究增加了临界质量和严格性。 总的来说，我们的团队可以从核医学，细胞和分子方面的一系列潜水员中汲取灵感 生物学，放射生物学，XFM，辐射保护和缓解，正常组织放射生物学和免疫学。我们 理想的位置是进行提出的研究，以解决A 全面而整合的方式。我们的希望是对生物学后果的重要见解 内部辐射发射器与现实生活中的偶然和附带暴露情况有关， 不能使用常规外束辐射或核医学方法对建模。但是， 辐射受损的细胞与组织之间相互作用的概念，危险信号传导， 免疫系统和恢复道路的参与可能适用于更广泛的背景。