Combined Target Therapy for the Pulmonary Syndrome

说明(由申请人提供)：鉴于恐怖主义风险加剧的现状，在发生大规模放射性或核事件后，迫切需要快速获得和易于分发的反措施作为减震剂。由于我们照顾急性意外(或故意)接触的受害者的能力增强，意味着接触者更有可能在全身暴露引起的直接血液危机中幸存下来，尽管如此，晚期发病率仍将作为多器官功能障碍综合征的一部分发生。因此，肺等器官在本综合征发展过程中的下游作用日益受到关注。虽然肺部后遗症(肺炎和纤维化)的总体进展是公认的，但导致其发展的途径的复杂性，包括细胞、分子和时间成分，导致我们的小组认为，没有任何单一的药物或策略可能是针对这些潜在致命终点的有效缓解或治疗。因此，我们设计了一个系统的实验设计，使用相关的“2-品系”小鼠模型，在该模型中，我们将评估包括基础广泛的抗炎药物和一些替代药物的联合治疗，每一种药物都被选为其在肺晚期效应进展中的已知靶点。此外，将根据急性和慢性治疗方法对这些组合进行评估。我们预计，到筹资期间结束时，我们将确定一种或多种组合疗法，每种疗法都有明确的剂量方法，可能会被开发用于放射事件后的即时和延迟期。

DESCRIPTION (provided by applicant): In light of the current state of heightened terrorism risk, rapidly accessible and easily distributed countermeasures are urgently required as mitigators following a mass radiological or nuclear event. Since our increased ability to care for victims of acute accidental (or intentional) exposure means that exposed persons are more likely to survive the immediate hematological crises which result from whole body exposure, nonetheless late morbidities will still occur as part of a multi-organ dysfunction syndrome. Therefore, the downstream roles played by such organs as the lung in this syndrome's progression are of increasing concern. Although the overall progression to pulmonary late effects (pneumonitis and fibrosis) is well recognized, the complex nature of the pathways leading to their development, which includes cellular, molecular and temporal components, has led to our group's contention that no single agent or strategy is likely to be an effective mitigator or treatment against these potentially lethal endpoints. We have therefore devised a systematic experimental design, using a pertinent "2-strain" murine model, in which we will assess combination therapies that include a broad-based anti-inflammatory together with a number of alternative agents, each of which has been chosen for its known target within the pulmonary late effect progression. In addition, these combinations will be assessed in terms of an acute versus a chronic treatment approach. We anticipate that by the end of the funding period, we will have identified one or more combination therapies, each with defined dosing approaches, that could potentially be developed for use in both the immediate and delayed periods following a radiological event.