Pulmonary response to external and internal exposure: model for dispersion event

对外部和内部暴露的肺部反应：弥散事件模型

• 批准号: 7678003
• 负责人: Jacob N Finkelstein
• 金额: $ 64.89万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7678003
• 关键词: Address; Adult; Aerosols; Animals; Area; Bone Marrow; Breathing; Caliber; Cells; Cesium; Characteristics; Chemicals; Child; Childhood; Condition; Cytokine Activation; Data; Deposition; Depth; Development; Devices; Dose; Event; Exposure to; Genetic; Goals; Growth; Growth Factor; Immune; Immune system; Inflammatory; Investigation; Isotopes; Label; Late Effects; Liver; Localized; Lung; Modeling; Molecular; Mus; Nature; Normal tissue morphology; Nuclear; Numbers; Organ; Organism; Particulate; Pharmaceutical Preparations; Physiological; Population; Procedures; Prostaglandins; Purpose; Radiation; Radiation Tolerance; Radiation induced damage; Radio; Radioactive; Radioisotopes; Range; Recruitment Activity; Risk; Role; Route; Schedule; Site; Solubility; Spleen; Surface; Symptoms; System; Testing; Time; Tissues; Toxic effect; Work; base; body system; cell type; chemical property; chemokine; concept; cytokine; design; dirty bomb; injured; internal radiation; irradiation; mouse model; nanomaterials; nanoparticle; nanosized; particle; particle exposure; postnatal; pup; radiation effect; research study; response; size

The overall goal of this project is directed at gaining a deeper understanding of the basis for the normal tissue late effects that are observed in the lung at low external doses and in the whole body from the internal exposure that occurs as a result of a radiological and/or nuclear dispersion event. An important, but inadequately addressed, aspect of such an event is that radiation exposure can occur internally, and may be either systemic or highly localized depending on the physical and chemical nature of the radioactive material involved. Particles generated in such events will include a significant proportion of ultra-fine or nano-materials, which have different physical and chemical properties from particles of larger diameter and surface area. This phenomenon needs to be considered when calculating dose and potential target organ systems following particle exposure, and this will be addressed in Specific Aim 2 of this project. Our previous work with external beam irradiation of the lung has led to our paradigm of radiation late effects being dependent upon the "conversation" which takes place between a number of injured cells, rather than the classic concept of a single target cell. In the specific aims for this proposal, we will continue our studies of the lung, extending our examination to the lower doses more likely to be seen in the population after the detonation of a radiological device (Specific Aim 1). In the studies in Specific Aim 2, we will determine the effects of inhaled radionuclide nanoparticles and develop a model that compares such exposures to those observed after external lung irradiation alone, as well as whole body exposures. In the studies in Specific Aim 3, we will use information about the cellular and molecular events that occur following radiation exposure, particularly in terms of the alterations in expression of proinflammatory and profibrotic cytokines and growth factors in conjunction with their genetic context, to design and test agents that could be used to ameliorate the toxic effects of radiation in the lung. Finally, in the experiments in Specific Aim 4, we plan to address the question of the potential for altered sensitivity in the developing organism by examining the pulmonary responses following external beam and internal radiation exposures during postnatal growth.

该项目的总体目标是更深入地了解正常组织后期效应的基础，这些效应是在低外部剂量下在肺部观察到的，以及由于放射和/或核扩散事件而发生的内部暴露在整个身体中观察到的。此类事件的一个重要但未充分解决的方面是，辐射暴露可能发生在内部，并且可能是系统性的或高度局部性的，具体取决于所涉及的放射性物质的物理和化学性质。此类事件中产生的颗粒将包括很大比例的超细或纳米材料，它们具有与较大直径颗粒不同的物理和化学特性 和表面积。在计算颗粒暴露后的剂量和潜在靶器官系统时需要考虑这种现象，这将在本项目的具体目标 2 中得到解决。我们之前对肺部进行外束照射的工作导致我们的辐射后期效应范式依赖于多个受伤细胞之间发生的“对话”，而不是单个靶细胞的经典概念。在该提案的具体目标中，我们将继续对肺部进行研究，将我们的检查范围扩大到放射装置爆炸后更有可能在人群中出现的较低剂量（具体目标 1）。在具体目标 2 的研究中，我们将确定吸入放射性核素纳米粒子的影响，并开发一个模型，将此类暴露与仅外部肺部照射以及全身暴露后观察到的暴露进行比较。在具体目标 3 的研究中，我们将利用有关辐射暴露后发生的细胞和分子事件的信息，特别是促炎和促纤维化细胞因子和生长因子的表达变化及其遗传背景，来设计和测试可用于改善肺部辐射毒性作用的药物。最后，在具体目标 4 的实验中，我们计划通过检查出生后生长期间外部光束和内部辐射暴露后的肺部反应来解决发育中有机体敏感性可能改变的问题。