Initial characterization of a non-pharmacological radiation countermeasure

非药物辐射对策的初步表征

• 批准号: 8538389
• 负责人: JOSEPH R DYNLACHT
• 金额: $ 19.11万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538389
• 关键词: Acute; Adolescent; Adult; Age; Blood; Blood Cells; Bone Marrow; C57BL/6 Mouse; Cessation of life; Data; Development; Devices; Dose; Down-Regulation; Elements; Exposure to; Female; Gastrointestinal tract structure; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Ionizing radiation; Lead; Length; Lethal Dose 50; Life; Measurement; Mediating; Modeling; Molecular; Mus; Natural regeneration; Nuclear; Pattern; Plague; Production; Protocols documentation; Radiation; Radiation Syndromes; Radioprotection; Recovery; Relative (related person); Roentgen Rays; Safe Sex; Stem cells; Surgical incisions; Syndrome; Terrorism; Testing; Time; United States; Up-Regulation; age group; aged; biological adaptation to stress; cytokine; emergency service responder; intestinal epithelium; irradiation; male; mouse model; novel; precursor cell; prevent; protective efficacy; radiation effect; research study; sex; stem; subcutaneous; whole body irradiation effect; wound; young adult

DESCRIPTION (provided by applicant): A radiological terrorist attack (e.g., the detonation of an improvised nuclear device) could result in the exposure of thousands of civilians and first responders to lethal or potentially lethal doses of ionizing radiation (IR). Unfortunately, existin countermeasures are generally ineffective if administered after exposure or are effective only within a narrow dose range. In addition, there are logistical problems associated with the treatment of mass casualties using existing approaches. Thus, there is a major effort in the U.S. to develop countermeasures that would be effective if administered after irradiation, involve easy deployment and use protocols, and are non-toxic. We have identified a novel non-pharmacological strategy which is very effective at mitigating the lethal effects of IR in a female mouse model if administered after exposure, and satisfies many of the criteria of an ideal radiation countermeasure. Our approach involves the creation of a small subcutaneous incision (1 cm) in the mouse within a defined period of time post-irradiation. Our preliminary data suggest that subcutaneous wounding several minutes after irradiation greatly protects against lethality. Mitigation of IR effects and the acute radiation syndrome may be mediated by the modulation of specific cytokines or enhanced recovery of hematopoiesis. However, the optimal parameters for creating the wound to derive maximal radioprotection and the mechanism by which wounding protects against radiation lethality have yet to be elucidated. In this exploratory application, we seek to accomplish two main objectives. The first objective will be to determine the optimal parameters for subcutaneous wounding after irradiation (length of the wound, window of time after irradiation during which wounding is protective), and the maximum dose for which protection may be afforded. To establish the validity of the "protective wounding" strategy as a radiation countermeasure, and its usefulness in the treatment of mass casualties, we shall determine whether protection against lethality is afforded within a window of up to 48 h post-irradiation. To determine applicability, we will test our strategy on mice of both sexes and of various ages, and assess whether all age groups and both sexes are protected similarly from the lethal effects of IR. To accomplish this, the 30-day survival of mice that have received a wound will be compared with that of mice which were not wounded. The second objective will be to identify potential mechanisms by which wounding after irradiation enhances survival. Specifically we shall compare the temporal pattern of modulation of cytokine profiles, and damage to and recovery of blood elements (and precursors) and the gastrointestinal tract, in wounded and control irradiated mice, and correlate these observations with survival. In addition to demonstrating the validity and general applicability of this non- debilitating protective wounding strategy, the experiments proposed should lead to further development of both non-pharmacological and pharmacological radiation countermeasures.

描述（由申请人提供）：放射性恐怖袭击（例如简易核装置的爆炸）可能导致数千名平民和急救人员暴露于致命或可能致命剂量的电离辐射（IR）。不幸的是，现有的对策如果在暴露后施用通常是无效的，或者仅在狭窄的剂量范围内有效。此外，使用现有方法治疗大规模伤亡人员还存在后勤问题。因此，美国正在大力开发对策，这些对策在辐射后实施将是有效的，涉及易于部署和使用的协议，并且是无毒的。我们已经确定了一种新颖的非药物策略，可以非常有效地减轻 IR 对女性的致命影响 如果在暴露后施用，则可以建立小鼠模型，并且满足理想辐射对策的许多标准。我们的方法包括在辐射后规定的时间内在小鼠中创建一个小皮下切口（1 厘米）。我们的初步数据表明，照射后几分钟的皮下损伤可以极大地防止致命。 IR效应和急性辐射综合征的减轻可以通过调节特定细胞因子或增强造血功能的恢复来介导。然而，创造伤口以获得最大辐射防护的最佳参数以及伤口防止辐射致死的机制尚未阐明。在这个探索性应用中，我们力求实现两个主要目标。第一个目标是确定照射后皮下伤口的最佳参数（伤口长度、照射后伤口具有保护作用的时间窗口）以及可提供保护的最大剂量。为了确定“保护性伤害”策略作为辐射对抗措施的有效性及其在治疗大规模伤亡中的有用性，我们将确定是否在辐射后长达 48 小时的窗口内提供针对致命性的保护。为了确定适用性，我们将在两种性别和不同年龄的小鼠身上测试我们的策略，并评估所有年龄组和两种性别是否都受到类似的保护，免受红外线的致命影响。为了实现这一目标，将受伤小鼠与未受伤小鼠的 30 天存活率进行比较。第二个目标是确定辐射后受伤提高生存率的潜在机制。具体来说，我们将比较受伤小鼠和对照受辐射小鼠中细胞因子谱调节的时间模式以及血液元素（和前体）和胃肠道的损伤和恢复，并将这些观察结果与生存相关联。除了证明这种非衰弱性保护性伤害策略的有效性和普遍适用性之外，所提出的实验还应导致非药物和药物辐射对策的进一步发展。

项目成果

Characterization and Etiology of Swollen Muzzles in Irradiated Mice.

受辐射小鼠口鼻肿胀的特征和病因学。

• DOI: 10.1667/rr14724.1
• 发表时间: 2019
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Garrett,Joy;Sampson,CarolH;Plett,PArtur;Crisler,Robin;Parker,Jeffrey;Venezia,Richard;Chua,HuiLin;Hickman,DebraL;Booth,Catherine;MacVittie,Thomas;Orschell,ChristieM;Dynlacht,JosephR
• 通讯作者: Dynlacht,JosephR