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

该项目的总体目标是更深入地了解由于辐射和/或核扩散事件而发生的内部照射在低外部剂量下在肺和全身观察到的正常组织迟发效应的基础。这类事件的一个重要但没有得到充分解决的方面是，辐射暴露可能发生在内部，可能是系统性的，也可能是高度局部性的，这取决于所涉及的放射性材料的物理和化学性质。在这样的事件中产生的粒子将包括相当大比例的超细或纳米材料，它们具有与较大直径的粒子不同的物理和化学性质 和表面积。在计算颗粒物暴露后的剂量和潜在靶器官系统时，需要考虑这一现象，这将在本项目的具体目标2中解决。我们之前在肺外照射方面所做的工作导致了我们的辐射迟发效应的范例依赖于发生在多个受损细胞之间的“对话”，而不是单个靶细胞的经典概念。在这项提案的具体目标中，我们将继续我们对肺的研究，将我们的检查扩大到在放射设备爆炸后更有可能在人群中看到的较低剂量(具体目标1)。在特定目标2的研究中，我们将确定吸入放射性核素纳米颗粒的影响，并开发一个模型，将这种暴露与仅在肺外照射后观察到的暴露以及全身暴露进行比较。在具体目标3的研究中，我们将利用辐射暴露后发生的细胞和分子事件的信息，特别是促炎症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减轻辐射对肺的毒性影响的制剂。最后，在特定目标4的实验中，我们计划通过检查出生后生长期间外照射和内照射后的肺反应，来解决发育中有机体的敏感性改变的可能性的问题。

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.