Triterpenoids in mitigation of radiation induced acute or delayed inflammation

项目摘要 目前，需要减轻急性和延迟辐射综合征的战略。风险大 遭受辐射照射的人口是真实的，而且还在增加。辐射诱发的炎症 在诱发辐射毒性中的重要作用。趋化因子信号传导在全身和局部发挥关键作用 通过调节炎性免疫细胞如炎性单核细胞的流出和募集来调节炎症 和T细胞。辐射暴露诱导炎症细胞的募集，并促进全身和局部 炎症我们已经观察到，在小鼠中表达趋化因子受体2的基因的缺失促进了 抗辐射引起急性和迟发性炎症反应。三萜类化合物是非常有效的抗炎药 剂.最近的研究结果表明，合成的油酸衍生物， 炎症介质如趋化因子配体2的产生。根据NIAID化学对策 研究计划（CCRP）三萜类化合物如CDDO-甲酯（CDDO-Me）已经显示出减轻 NRF 2依赖性化学性眼损伤在本建议书中，我们会研究《儿童发展及歧视条例》的影响- ME对小鼠急性和迟发性放射性炎症的保护作用 诱发胃肠道综合征和放射性肺综合征。我们还将 表征CDDO-Me在调节骨髓源性炎性免疫细胞中的作用 在受伤的组织中进行招募。确定CDDO-Me的作用机制将有助于CDDO-Me作为药物 根据FDA的动物法规，

Project Summary Currently, there is a need for strategies that mitigate acute and delayed radiation syndrome. The risk of large populations encountering radiation exposure is real and growing. Radiation induced inflammation plays significant role in inducing radiation toxicity. Chemokine signaling plays key role in systemic and local inflammation by modulating egress and recruitment inflammatory immune cells such as inflammatory monocytes and T cells. Radiation exposure induces recruitment of inflammatory cells and promotes systemic and local inflammation. We have observed that deletion of genes expressing chemokine receptor 2 in mice promotes resistance radiation induced acute and delayed inflammation. Triterprenoids are very potent anti-inflammatory agents. Recent findings suggest that synthetic derivatives of oleanolic acid that are more potent at suppressing production of the inflammatory mediator such as chemokine ligand 2. Under NIAID Chemical Countermeasures Research Program (CCRP) Triterprenoids such as CDDO- methyl ester (CDDO-Me) has been shown to mitigate chemical induced ocular injury by nrf2 dependent manner. In this proposal we will examine the effect of CDDO- Me against radiation induced acute and delayed inflammation using mice model of radiation induced gastrointestinal syndrome and radiation induced pulmonary syndrome respectively. We will also characterize the effect of CDDO-Me in modulation of bone marrow derived inflammatory immune cell recruitment in injured tissue. Determination of mechanism of action of will facilitate CDDO-Me as a medical countermeasure against radiation under the FDA’s Animal Rule.