Project Summary Supplement title: Modulation of chemokine signaling to mitigate radiation induced Paneth cell dysfunction The risk of large populations encountering radiation exposure is real and growing. Currently, there is a need for strategies that mitigate gastrointestinal acute radiation syndrome. Radiation induced intestinal injury results from loss of intestinal stem cell and dysregulation of intestinal stem cell niche. Paneth cells (PCs) located at the bottom of small intestinal crypts are very critical member in ISC niche regulating ISC homeostasis through various signaling pathways and growth factors. Moreover, PCs are involved in mucosal immunity by secreting antimicrobial proteins, such as α-defensins. α-Defensins are a family of cationic peptides that form an integral part of the innate immune system. Macrophages are important for repair and regeneration of intestinal epithelium following irradiation. However, involvement of myeloid/ macrophages in radiation induced PC dysfunction is not known. Radiation exposure induces recruitment of inflammatory monocytes and promotes systemic and local inflammation. We have observed that modulation of chemokine receptor 2 signaling alters intestinal macrophage population and mitigates GI-ARS. In this proposal by modulating CCR2/CCL2 axis with CCR2 inhibitor we will determine the macrophage phenotype involved in regulation of PCs radiosensitivity. We will determine PCs survival and PC derived paracrine signals in mice model of GI-ARS receiving CCR2 inhibitor. Determination of mechanism of action will facilitate CCR2 inhibitor as a medical countermeasure against radiation under the FDA’s Animal Rule.