Page 75 - 2014 Printable Abstract Book
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that Astronauts will experience some level of HICI during deep space missions; however, there is
considerable inter-individual susceptibility to developing HICI, with ~30-50% of rats showing apparently
normal behavioral (spatial memory) performance after exposure to 20 cGy 1 GeV/u 56Fe while the
remaining rats are unable to perform the task. This phenomenon provides a unique opportunity to gain
insight into the factors that lead to HICI, and perhaps more importantly, those that prevent its emergence.
Ultimately, memory and learning are a reflection of the functionality of the neurons, and thus any process
that interferes with the ability of neurons to encode, store, and retrieve memories will impact upon
cognitive performance. The impairment of a particular behavioral task can accrue by either: 1) loss of
neurons; 2) loss of functionality of the individual neurons; 3) loss of co-ordination of the neural network
in the region of the brain that regulates that task; or 4) a combination of all three. To date investigators
have tried to elucidate how HZE exposure leads to HICI by highly targeted studies on single
neurophysiological processes e.g., release of neurotransmitters or electrophysiology of synapses.
However, such processes, even if altered, do not occur in isolation, and thus do not provide the complete
(systems biology) basis for the induction of HICI. To help elucidate what processes are differentially altered
in rats that exhibit impaired or apparently normal spatial memory following exposure to 20 cGy of 1 GeV/n
56Fe particles, we have characterized the composition of the hippocampal proteome using a “shot-gun”
proteomic profiling approach. RESULTS: Our preliminary findings suggest that there is persistent oxidative
stress (alterations in the proteosome and the COP9 signalosome), altered adenosine metabolism
(elevated adenosine kinase levels), ongoing autophagy (MAPILC3B) and altered synaptic plasticity (SYNPO,
STX12, CALB2, CTTN, HPCAL4) in the irradiated hippocampus, irrespective of the spatial memory
performance status. The ultimate behavioral phenotype appears to be determined by how well the
hippocampal neurons compensate to the on-going oxidative stress and associated side-effects. The
neuroproteome of irradiated rats that have poor spatial memory includes proteins that are known to be
associated with poor spatial memory performance (FUS, SIRT2), enhance neuronal loss (FUS, SIRT2) and
apoptosis (HTRA2), enhance levels of synaptic plasticity and dendritic remodeling (NCAM1, CRK2,
ARFGAP1) and possibly amyloidosis, and some other aspects of Alzheimer’s disease. SUMMARY: The
various technical procedures used in the shot-gun proteomic profiling (using the Q-Exactive hybrid
quadrupole-Orbitrap Mass Spectrometer platform) will be described, as well as the data mining
techniques of the initial proteomic screen data, and how the output from such data can be used to develop
highly targeted interrogation approaches of the processes implicated in HICI. Such refinements alter shot-
gun proteomic profiling studies from a “fishing exercise” to a “logic-guided interrogation” of the
neuroproteome”, and will help provide clues to the underlying mechanism of HICI.
(S1902) The role of CCR2 on neuronal function after cranial irradiation. Susanna Rosi, University of
California San Francisco, San Francisco, CA
Therapeutic irradiation is commonly used to treat primary or metastatic central nervous system tumors.
It is believed that activation of neuroinflammatory signaling pathways contributes to the development of
common adverse effects, which may ultimately contribute to cognitive dysfunction. Our recent studies
identified the chemokine (C-C motif) receptor (CCR2), constitutively expressed by cells of the monocyte-
macrophage lineage, as a mediator of cognitive impairments induced by irradiation (Belarbi et al., 2013
Cancer Research ). In the present study we utilized a unique reporter mouse (CCR2RFP/+CX3CR1GFP/+)
to accurately delineate the resident (CX3CR1+) versus peripheral (CCR2+) innate immune response in the
brain following cranial irradiation. Our results demonstrate that a single dose of 10Gy cranial γ-irradiation
73 | P a g e
considerable inter-individual susceptibility to developing HICI, with ~30-50% of rats showing apparently
normal behavioral (spatial memory) performance after exposure to 20 cGy 1 GeV/u 56Fe while the
remaining rats are unable to perform the task. This phenomenon provides a unique opportunity to gain
insight into the factors that lead to HICI, and perhaps more importantly, those that prevent its emergence.
Ultimately, memory and learning are a reflection of the functionality of the neurons, and thus any process
that interferes with the ability of neurons to encode, store, and retrieve memories will impact upon
cognitive performance. The impairment of a particular behavioral task can accrue by either: 1) loss of
neurons; 2) loss of functionality of the individual neurons; 3) loss of co-ordination of the neural network
in the region of the brain that regulates that task; or 4) a combination of all three. To date investigators
have tried to elucidate how HZE exposure leads to HICI by highly targeted studies on single
neurophysiological processes e.g., release of neurotransmitters or electrophysiology of synapses.
However, such processes, even if altered, do not occur in isolation, and thus do not provide the complete
(systems biology) basis for the induction of HICI. To help elucidate what processes are differentially altered
in rats that exhibit impaired or apparently normal spatial memory following exposure to 20 cGy of 1 GeV/n
56Fe particles, we have characterized the composition of the hippocampal proteome using a “shot-gun”
proteomic profiling approach. RESULTS: Our preliminary findings suggest that there is persistent oxidative
stress (alterations in the proteosome and the COP9 signalosome), altered adenosine metabolism
(elevated adenosine kinase levels), ongoing autophagy (MAPILC3B) and altered synaptic plasticity (SYNPO,
STX12, CALB2, CTTN, HPCAL4) in the irradiated hippocampus, irrespective of the spatial memory
performance status. The ultimate behavioral phenotype appears to be determined by how well the
hippocampal neurons compensate to the on-going oxidative stress and associated side-effects. The
neuroproteome of irradiated rats that have poor spatial memory includes proteins that are known to be
associated with poor spatial memory performance (FUS, SIRT2), enhance neuronal loss (FUS, SIRT2) and
apoptosis (HTRA2), enhance levels of synaptic plasticity and dendritic remodeling (NCAM1, CRK2,
ARFGAP1) and possibly amyloidosis, and some other aspects of Alzheimer’s disease. SUMMARY: The
various technical procedures used in the shot-gun proteomic profiling (using the Q-Exactive hybrid
quadrupole-Orbitrap Mass Spectrometer platform) will be described, as well as the data mining
techniques of the initial proteomic screen data, and how the output from such data can be used to develop
highly targeted interrogation approaches of the processes implicated in HICI. Such refinements alter shot-
gun proteomic profiling studies from a “fishing exercise” to a “logic-guided interrogation” of the
neuroproteome”, and will help provide clues to the underlying mechanism of HICI.
(S1902) The role of CCR2 on neuronal function after cranial irradiation. Susanna Rosi, University of
California San Francisco, San Francisco, CA
Therapeutic irradiation is commonly used to treat primary or metastatic central nervous system tumors.
It is believed that activation of neuroinflammatory signaling pathways contributes to the development of
common adverse effects, which may ultimately contribute to cognitive dysfunction. Our recent studies
identified the chemokine (C-C motif) receptor (CCR2), constitutively expressed by cells of the monocyte-
macrophage lineage, as a mediator of cognitive impairments induced by irradiation (Belarbi et al., 2013
Cancer Research ). In the present study we utilized a unique reporter mouse (CCR2RFP/+CX3CR1GFP/+)
to accurately delineate the resident (CX3CR1+) versus peripheral (CCR2+) innate immune response in the
brain following cranial irradiation. Our results demonstrate that a single dose of 10Gy cranial γ-irradiation
73 | P a g e
