Modulation of chemokine signaling to mitigate radiation induced 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。趋化因子信号转导在全身和局部 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 抗辐射性CCR2信号传导的药理学抑制减轻小鼠中的急性辐射综合征。 此外，接受CCR 2拮抗剂治疗的这些动物没有出现急性辐射的延迟效应 暴露（DEARE），如辐射诱发的肺综合征。在本提案中，我们将研究 CCR2抑制剂对辐射诱导的急性和迟发性炎症的影响 迟发性辐射损伤我们将充分表征CCR2拮抗剂治疗，确定最佳治疗方案。 减轻辐射诱导的急性和延迟炎症的剂量和时间表。我们会研究 该策略在年轻和老年动物中的普遍适用性。我们还将描述CCR 2的作用， 拮抗剂在调节骨髓源性炎性免疫细胞释放和募集中的作用 组织.确定将促进CCR2抑制剂作为医学对策的作用机制 根据食品药品管理局的动物条例

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 radiation resistance. Pharmacological inhibition of CCR2 signaling mitigates acute radiation syndrome in mice. Moreover these animals receiving CCR2 antagonist treatment did not develop delayed effect of acute radiation exposure (DEARE) such as radiation induced pulmonary syndrome. In this proposal we will examine the effect of CCR2 inhibitor against radiation induced acute and delayed inflammation using mice model of acute and delayed radiation injury. We will fully characterize CCR2 antagonist treatment with a determination of an optimum dose and schedule for mitigation of radiation induced acute and delayed inflammation. We will examine the general applicability of this strategy in young and aged animals. We will also characterize the effect of CCR2 antagonist in in modulation of bone marrow derived inflammatory immune cell release and recruitment in injured tissue. Determination of mechanism of action of will facilitate CCR2 inhibitor as a medical countermeasure against radiation under the FDA’s Animal Rule.