Modulation of chemokine signaling to mitigate radiation induced inflammation

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.