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的总体目标是将放射性核素照射和留下的元素特征与 暴露的生物标志物，无论是组织学的、细胞的还是分子的。我们这样做的动机源于 来自内部发射器的辐射在器官、组织和细胞中分布非常不均匀， 这一事实仍然鲜为人知。放射性核素分布的异质性取决于 与放射性核素本身和生物体对它的反应有关的一组复杂参数，例如 放射性核素半衰期、衰变模式、活性、浓度、粒度、形态、化学形式，以及 溶解性，而生物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体。 因为放射性核素暴露的体内足迹是多尺度的，例如，DNA损伤和细胞死亡 （亚）细胞水平或细胞/组织水平的趋化因子/细胞因子产生，其基本上意味着生物标志物 最好的记录是沿着相同的多维纳米，微米和中尺度， 上网为目标例如，微RNA表达将在免疫细胞浸润的背景下在免疫细胞中被记录。 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出， X射线荧光显微镜（XFM）作为放射性核素绘图的有力工具， 我们的方法。应用XFM技术来探索西北大学令人难以置信的丰富资源， 辐射动物（ARMA）档案，与当代动物模型相结合，为我们提供了独特的机会 追溯放射性核素暴露的生物后果，并开辟了生物标志物的道路， 并最终减轻发现的风险。大量动物的犬和鼠组织 各种放射性核素和在不同的时间增加临界质量和严谨性，我们的研究。 总的来说，我们的团队可以从核医学、细胞和分子医学的各种专业知识中汲取经验， 生物学、放射生物学、XFM、辐射防护和缓解、正常组织放射生物学和免疫学。我们 是开展拟议研究的理想场所， 全面和综合的方式。我们的希望是获得重要的见解， 与真实的生活中的意外和偶然暴露场景相关的内部辐射发射器， 不能使用常规的外部射束辐射或核医学方法来建模。然而 辐射损伤细胞和组织之间相互作用的基本概念，危险信号， 免疫系统的参与和恢复之路可能适用于更广泛的背景。