Modulation of chemokine signaling to mitigate radiation induced inflammation

项目摘要 目前，需要制定减轻急性和延迟辐射综合征的策略。风险很大， 遭遇辐射暴露的人口是真实存在的，而且还在不断增长。辐射致炎作用 在诱发辐射毒性方面的重要作用。趋化因子信号在全身和局部发挥关键作用 通过调节外流和募集炎性免疫细胞(如炎性单核细胞)来实现炎症 和T细胞。辐射可诱导炎性细胞募集，促进全身和局部 发炎。我们观察到，小鼠体内表达趋化因子受体2的基因的缺失促进了 耐辐射。药理抑制CCR2信号可减轻小鼠的急性辐射综合征。 此外，这些接受CCR2拮抗剂治疗的动物没有出现急性辐射的延迟效应 暴露(DEARE)，如放射性肺综合征。在这项建议中，我们将研究其影响 CCR2抑制剂抗放射性急性和迟发性炎症的实验研究 延迟性辐射损伤。我们将通过确定最佳的CCR2拮抗剂治疗来全面描述CCR2拮抗剂的治疗 减轻辐射引起的急性和延迟性炎症的剂量和时间表。我们将研究 这一策略在幼年和老年动物中的普遍适用性。我们还将描述CCR2的影响 拮抗剂对损伤后骨髓炎性免疫细胞释放和募集的调节作用 组织。Will促进CCR2抑制剂作为药物对策的作用机制的确定 根据美国食品和药物管理局的动物规则，防止辐射。

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.