Skin & Immunology - Mitigation of Radiation and Combined Injury to the Skin

项目总结（见说明）： 美国仍然是生物恐怖主义的目标，特别是放射性袭击。这个真实的 这种可能性促使人们需要采取对策，防止辐射中毒的生物效应。 日本和切尔诺贝利核辐射事件的历史数据表明， 接触会大大增加个人的发病率和死亡率。皮肤是至关重要的， 防止有害物质和防止病原体攻击;这两个参数肯定是 在辐射引发的破坏后受损在上一个融资周期中，我们的团队 在破译皮肤辐射的急性和慢性影响的关键机制方面取得了进展，即 辐射诱导的树突状细胞（DC）耗竭和氧化应激的中枢管理。这些机械数据 已经导致发现减轻上述辐射影响的潜在试剂。这项建议会 进一步阐明我们在初步研究中发现的缺陷的性质，为多器官策略提供基础 以减轻损害。这些研究将大大受益于与其他项目的互动，特别是骨骼 作为对其他器官系统的影响的研究无疑会影响皮肤的免疫功能。 该提案将探讨单独或与额外的皮肤损伤相结合的辐射如何损害特定的皮肤损伤。 皮肤稳态功能所必需的参数。在目标1中，我们将探索机制和功能 辐射引起的皮肤DC耗竭的后果;我们认为这种现象将使个体 暴露于入侵的皮肤病原体。更重要的是，我们将解决各种代理人的影响， 减轻这种损失。目标2将检验辐射暴露损害皮肤屏障功能的假设， ROS介导的损伤和过度炎症反应，加重继发性皮肤损伤修复的负担。 将检测缓解剂在恢复动物功能和减少损伤方面的疗效。目标3将侧重于 辐射对特殊人群，即儿童或青少年的影响。特别是，我们将研究 年轻时的辐射暴露是否会导致慢性屏障缺陷， 生活将在tils模型中测试在目标1和2中发现有效的缓解措施的效用。

PROJECT SUMMARY (See instructions): The United States continues to be a target of bioterrorism especially in the form of a radiological attack. This real possibility has prompted the need for countermeasures to protect against the biological effects of radiation poisoning. Historical data from radiation events in Japan and Chernobyl indicate that skin injury in conjunction with radiation exposure greatly increases both morbidity and mortality rates in individuals. The skin is vital in providing a ban-ier against harmful substances and protecting against pathogenic attack; two parameters that would certainly be compromised following a radiation-induced breach in this ban-ier. In the previous funding cycle, our group has made strides in deciphering key mechanisms responsible for acute and chronic effects of radiation in the skin, namely radiation-induced dendritic cell (DC) depletion and epidemnal management of oxidative stress. This mechanistic data has lead to the discovery of potential agents that mitigate the above-mentioned effects of radiation. This proposal will further clarify the nature of the defects discovered in our initial studies to provide a foundation for multi-organ strategies for mitigating damage. These studies will greatly benefit from interactions with the other projects, particulariy the bone man-ow studies as effects on otiier organ system will undoubtedly affect immune functions in the skin. This proposal will explore how radiafion alone or in combination with an additional skin injury will impair particular parameters essenfial to homeostatic function of the skin. In Aim 1, we will explore the mechanism and functional consequences of radiation-induced cutaneous DC depletion; a phenomenon we believe will leave the individual exposed to invading cutaneous pathogens. More importantly, we will address the impact of various agents in mitigating this loss. Aim 2 will test the hypothesis that radiation exposure impairs skin banier function resulting from ROS-mediated damage and a hyperinflammatory response, which burdens the repair of secondary skin injury. Mitigating agents will be tested for their efficacy in restoring bamer function and reducing injury. Aim 3 will focus on the effects of radiation on special populations i.e. those of pediatric or adolescent age. In particular, we will examine whether radiation exposure at a young age results in a chronic barrier defect that impairs normal skin function later in life. The utility of mitigators found efficacious in Aims 1 and 2 will be tested in tills model.