Final Report of project entitled "A metabolomics and mouse models approach to study inflammatory and immune responses to radiation"

The three-year project entitled ?A Metabolomics and Mouse Models Approach to Study Inflammatory and Immune Responses to Radiation? was initiated in September 2009. The overall objectives of this project were to investigate the acute and persistent effects of low dose radiation on T cell lymphocyte function and physiology, as well the contributions of these cells to radiation-induced inflammatory responses. Inflammation after ionizing radiation (IR), even at low doses, may impact a variety of disease processes, including infectious disease, cardiovascular disease, cancer, and other potentially inflammatory disorders. There were three overall specific aims: 1. To investigate acute and persistent effects of low dose radiation on T cell subsets and function; 2. A genetic approach with mouse models to investigate p38 MAPK pathways that are involved in radiation-induced inflammatory signaling; 3. To investigate the effect of radiation quality on the inflammatory response. We have completed the work proposed in these aims. Below are our major accomplishments: ? Our data show that T cells from low dose irradiated animals have lower proliferation potency and cytokine production upon T cell receptor (TCR) stimulation. This effect was observed as early as 4 hours after radiation, and lasted up to two weeks. ? Using our ultraperformancemore » liquid chromatography coupled with highly sensitive time-of-flight mass spectrometry (UPLC-QTOF) metabolomics method, we demonstrated the global changes of metabolites in T cells upon TCR stimulation in a time-dependent pattern. ? We found that the TCR activation induced metabolome changes are remarkably altered in a dose-dependent manner after radiation. At a dose of 0.5 Gy and above, IR mitigated TCR activation induced metabolome changes while at the dose of as low as 0.1Gy IR had a mild stimulatory effect on some of the metabolome changes. ? We revealed the mechanism for how radiation affects T cell activation by showing that the energy supply pathways in activated T cells are greatly compromised after radiation. ? We demonstrated that low dose ionizing radiation has a variety of effects on different T cell subsets, and p38 plays an important role in these effects. ? The study with low dose proton radiation shows similar effects on T cell proliferation upon TCR activation. Our dose rate study with proton radiation indicates that at low dose rates, proton exposure has less detrimental effects on T cell activation. ? We have one published paper and several manuscripts submitted or in preparation. ? We presented our findings at multiple DOE low dose program workshops, RRS annual meetings and other conferences. Our project is the first to apply a cutting-edge metabolomics approach to study the effects of radiation on immune cell function. Our findings demonstrate that metabolomics is a powerful method, which not only has higher sensitivity than the classical immune cell biology endpoints, but also helps to reveal the underlying mechanisms providing evidence that T cell activation is a metabolically dynamic process. Our T cell subset study sheds light on the effects of radiation on different T cell subsets and relevant signaling pathways mediating these effects. We have proved that our metabolomics platform and the T cell subset differentiation methods are useful and informative approaches for investigation and assessment of immune cell function after radiation. Our mechanistic findings on metabolic pathways may help to identify potential targets for intervention.« less