Page 195 - 2014 Printable Abstract Book
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of age. Data collected thus far indicate that mice irradiated with 0.4 Gy of 240 MeV/n Si or 600 MeV/n
56 Fe ions survive longer than mice irradiated with 3 Gy of gamma rays, but not as long as unirradiated
controls. The gamma ray irradiated mice have higher incidences of myeloid leukemia and thymic
lymphoma than HZE ion irradiated mice or unirradiated controls. Radiation of either quality increased the
risk for pituitary adenoma, brain tumors, Harderian gland tumors and ovarian tumors, but the data is too
preliminary to determine which radiation quality is most effective in inducing these solid tumors. In this
outbred population, thymic lymphomas, hepatocellular carcinomas and Harderian gland tumors each
appear to cluster within mice that are closely related. Radiation induced ocular changes in the mice are
being followed by dilated slit lamp examination and visual deficits by Virtual Optomotry Testing. As
expected, progressive, radiation associated lens changes are noted in exposed populations. In addition,
all of the mice have been phenotyped for radiation-induced cognitive changes using hippocampus-
dependent contextual and hippocampus-independent cued fear conditioning testing. Each mouse is being
genotyped for ~78,000 SNP markers and the data will be used to localize the genetic factors that
predispose individuals to specific spontaneous tumors, gamma ray-induced tumors and HZE ion-induced
tumors, and determine their overlap. The SNP genotypes will also be used to identify loci that control
susceptibilities to cognitive and ocular effects. Overlaps in susceptibility loci between radiation qualities
would suggest overlaps in injury or tumorigenesis pathways. Our preliminary analysis of cognitive deficits
based on 600 mice show that prior to radiation exposure we can classify cognitive outcomes based solely
on genotype information and that we can select individuals less likely to be affected by radiation. Funded
by NNX12AB54G from the National Aeronautics and Space Administration.
(PS3-10) Ionizing radiation impacts functional T Cell Receptor (TCR) activation accompanied by altered
1
1; 2
1
1
metabolic reprogramming. Henghong Li ; Yi-Wen Wang ; Bin Zhou ; and Albert J. Fornace Georgetown
1
University, Washington, DC and Institute of Radiation Medicine Chinese Academy of Medical Sciences,
2
Tianjin, China
The objective of this study is to investigate acute and persistent effects of ionizing radiation (IR)
on T cell activation and function. T cell is one of the most radiosensitive cell types in vivo and radiation is
known to impact CD4 T cells long term. T cells are normally activated by the specific antigen, which triggers
differentiation to subsets relying on the various cytokine environment. In addition, T cells have a well-
characterized cellular program upon activation by T-cell receptor (TCR) signaling that is reflected by major
changes in metabolism. Our study showed that T cells isolated from 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 to two weeks. Using our ultraperformance liquid
chromatography coupled with highly sensitive time-of-flight mass spectrometry (UPLC-QTOF)
metabolomics method, we demonstrated that the TCR activation induced metabolomic changes are
remarkably altered in a dose-dependent manner after radiation. At a dose of 0.5 Gy and above, IR
inhibited TCR activation induced metabolome changes while at the dose of as low as 0.1Gy IR had a mild
stimulatory effect on some of these changes. The results also showed that low dose ionizing radiation has
a variety of effects on differentiation of T cell subsets, and p38 plays an important role in these effects.
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 approach, which not
only has higher sensitivity than the classical immune cell biology methods, but also offers a mechanistic
understanding for T cell activation from the perspective of metabolites by showing the dynamic process
193 | P a g e
of age. Data collected thus far indicate that mice irradiated with 0.4 Gy of 240 MeV/n Si or 600 MeV/n
56 Fe ions survive longer than mice irradiated with 3 Gy of gamma rays, but not as long as unirradiated
controls. The gamma ray irradiated mice have higher incidences of myeloid leukemia and thymic
lymphoma than HZE ion irradiated mice or unirradiated controls. Radiation of either quality increased the
risk for pituitary adenoma, brain tumors, Harderian gland tumors and ovarian tumors, but the data is too
preliminary to determine which radiation quality is most effective in inducing these solid tumors. In this
outbred population, thymic lymphomas, hepatocellular carcinomas and Harderian gland tumors each
appear to cluster within mice that are closely related. Radiation induced ocular changes in the mice are
being followed by dilated slit lamp examination and visual deficits by Virtual Optomotry Testing. As
expected, progressive, radiation associated lens changes are noted in exposed populations. In addition,
all of the mice have been phenotyped for radiation-induced cognitive changes using hippocampus-
dependent contextual and hippocampus-independent cued fear conditioning testing. Each mouse is being
genotyped for ~78,000 SNP markers and the data will be used to localize the genetic factors that
predispose individuals to specific spontaneous tumors, gamma ray-induced tumors and HZE ion-induced
tumors, and determine their overlap. The SNP genotypes will also be used to identify loci that control
susceptibilities to cognitive and ocular effects. Overlaps in susceptibility loci between radiation qualities
would suggest overlaps in injury or tumorigenesis pathways. Our preliminary analysis of cognitive deficits
based on 600 mice show that prior to radiation exposure we can classify cognitive outcomes based solely
on genotype information and that we can select individuals less likely to be affected by radiation. Funded
by NNX12AB54G from the National Aeronautics and Space Administration.
(PS3-10) Ionizing radiation impacts functional T Cell Receptor (TCR) activation accompanied by altered
1
1; 2
1
1
metabolic reprogramming. Henghong Li ; Yi-Wen Wang ; Bin Zhou ; and Albert J. Fornace Georgetown
1
University, Washington, DC and Institute of Radiation Medicine Chinese Academy of Medical Sciences,
2
Tianjin, China
The objective of this study is to investigate acute and persistent effects of ionizing radiation (IR)
on T cell activation and function. T cell is one of the most radiosensitive cell types in vivo and radiation is
known to impact CD4 T cells long term. T cells are normally activated by the specific antigen, which triggers
differentiation to subsets relying on the various cytokine environment. In addition, T cells have a well-
characterized cellular program upon activation by T-cell receptor (TCR) signaling that is reflected by major
changes in metabolism. Our study showed that T cells isolated from 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 to two weeks. Using our ultraperformance liquid
chromatography coupled with highly sensitive time-of-flight mass spectrometry (UPLC-QTOF)
metabolomics method, we demonstrated that the TCR activation induced metabolomic changes are
remarkably altered in a dose-dependent manner after radiation. At a dose of 0.5 Gy and above, IR
inhibited TCR activation induced metabolome changes while at the dose of as low as 0.1Gy IR had a mild
stimulatory effect on some of these changes. The results also showed that low dose ionizing radiation has
a variety of effects on differentiation of T cell subsets, and p38 plays an important role in these effects.
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 approach, which not
only has higher sensitivity than the classical immune cell biology methods, but also offers a mechanistic
understanding for T cell activation from the perspective of metabolites by showing the dynamic process
193 | P a g e
