Role of Calcium/Calmodulin Dependent Kinase Kinase 2in Acute Radiation Syndrome. National Institutes of Health Pilot Grants Radccore 5U19-AI067798-07 (PI Luigi Racioppi).

The overall objective is to define the role of the Calcium/calmodulin-Dependent Kinase Kinase 2 (CaMKK2) in the innate response associated with acute-radiation syndrome (ARS). Although ARS is characterized by damages in areas where cells have a high turnover rate, experiences of most recent accidents uncover a severe systemic inflammatory response as major cause of the multi-organ dysfunction/failure syndrome (MODS/MOF), which involves damages also in lung, kidney and liver. Beside these detrimental consequences, the complex sequence of inflammatory events triggered by the radiation also promotes cytoprotective responses that limit the spread of damage and favor wound healing. The balance between these processes requires a concerted effort by resident tissue and inflammatory cell types, with macrophages apparently leading the way. Thereby, the current clinical approach to the treatment of the sub-syndromes ARS and MODS/MOF includes strategies aimed at attenuating the excessive systemic inflammatory response. Otherwise, to protect at-risk populations from major outbreaks of radiation-caused diseases, it has been proposed to use agents that activate the endogenous pathways of host defense, particularly ones that rapidly induce cytoprotective gene expression. This scenario indicates that fine-tuning of the innate response is crucial in preventing tissue and systemic damages caused by radiation. The current proposal builds upon the novel finding that CaMKK2 is selectively expressed in macrophages and required for their adhesion, phagocytosis and migration, as well as for the synthesis of chemokines involved in the recruitment of pro-inflammatory monocytes. These findings lead to the hypothesis that CaMKK2 plays a key role in mediating the cellular signals initiated by acute exposure to radiation, thereby its inhibition attenuates macrophage activation and reprograms the innate response toward cytoprotective pathways. In order to address this hypothesis, we will employ a genetically modified mouse model to explore the effect of CaMKK2 ablation on systemic inflammatory response and tissues damages in ARS. Moreover, we will evaluate the consequences of genetic ablation of CaMKK2 on radioprotective effects of certain TLRs agonist. The accomplishment of these aims will promote future studies aimed at exploring the effectiveness of CaMKK2 inhibitor, and the synergistic response of TLRs agonist/CaMKK2 inhibitor combinations in ARS.