Page 365 - 2014 Printable Abstract Book
P. 365
(PS7-22) TP508, a novel peptide, prevents radiation-induced damage to colonic crypts by rescuing loss
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of stemness and stimulating proliferation. Carla Kantara, PhD ; Stephanie Moya, BS ; Pomila Singh, PhD ;
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Courtney Houchen, MD, PhD ; and Darrell Carney, PhD ; UTMB, Galveston, TX and University of
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Oklahoma Health Sciences, Oklahoma City, OK
In recent years, the threat of radiation exposure has significantly increased. Nuclear threats
against the US and other countries have become a concern; hence the need to develop effective medicinal
countermeasures to mitigate effects of radiation exposure and prevent calamitous death rates caused by
accidental (Japan’s nuclear reactors) or intentional nuclear event. TP508 is an investigational drug which
has been shown to mitigate effects of whole body nuclear radiation (9Gy) in mice, and reduce
mortality/morbidity in irradiated mice. TP508 treatment post-exposure delayed mortality of mice exposed
to lethal doses of radiation (12Gy), and prevented radiation-induced apoptosis. Since radiation
significantly damages the intestines, we examined if TP508 exerted protective effects on
stemness/phenotype of intestinal crypts, which may contribute to the previously observed reduction in
mortality of irradiated mice treated with TP508. CD-1 (ICR) mice were exposed to whole body gamma
radiation (9Gy), or no radiation, followed by treatment of saline or TP508, 24 hrs post-irradiation. Mice
were euthanized 48hrs and 9 days post-exposure and colonic crypts were isolated and analyzed for their
length and architecture. Colons were processed for immunofluorescence and Western blot analysis for
stem cell populations expressing DCLK1, LGR5 and CD44 and examined for their proliferative/apoptotic
potential using PCNA/EdU and activated caspase-3 markers. Results demonstrated that lengths of colonic
crypts were significantly decreased in irradiated versus non-irradiated mice and treatment with TP508
reversed deleterious effects of irradiation on the morphology and colonic crypts lengths. Western blot
analysis for the indicated stem cell markers, strongly suggested that TP508 effectively protects against the
loss of stem cell populations in the colonic crypts of irradiated mice and increases proliferation. These
findings suggest that TP508 may protect stem cell populations from deleterious effects of irradiation, and
thus contribute towards reversing the damaging effects of irradiation on length/morphology of colonic
crypts by stimulating proliferation and decreasing apoptosis in crypts. We postulate that TP508 can be
developed as an effective novel drug for mitigation effects of radiation exposure.
(PS7-23) Endothelial cell responses in the hippocampus and cerebellum after irradiation to the young
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mouse brain. Martina Boström ; Marie Kalm ; Thomas Björk-Eriksson ; Nina Hellström Erkenstam ; and
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Klas Blomgren , Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden ; Institute
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of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden ; Department of
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Radiation Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden ; and Department of Women´s
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and Children´s Health, Karolinska Institute, Stockholm, Sweden
Cranial radiotherapy is essential in the treatment of malignant pediatric brain tumors, but it is
associated with long-term side effects, including cognitive decline, particularly in children. The underlying
cellular mechanisms are only partly known and the relative contribution of, for example, reduced
neurogenesis, perturbed myelination, astrogliosis, neuronal cell death, and vascular dysfunction, is a
matter of debate. In the current study we investigated the role the vasculature in cranial radiotherapy.
Postnatal day 14 mice received a single absorbed dose of 10 Gy whole brain irradiation (IR) and were
sacrificed 6 hours, 24 hours or 7 days post IR. Endothelial cells were isolated from the hippocampus and
from the cerebellum using fluorescence-activated cell sorting, followed by cell cycle analysis and gene
363 | P a g e
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of stemness and stimulating proliferation. Carla Kantara, PhD ; Stephanie Moya, BS ; Pomila Singh, PhD ;
1
2
1
Courtney Houchen, MD, PhD ; and Darrell Carney, PhD ; UTMB, Galveston, TX and University of
2
Oklahoma Health Sciences, Oklahoma City, OK
In recent years, the threat of radiation exposure has significantly increased. Nuclear threats
against the US and other countries have become a concern; hence the need to develop effective medicinal
countermeasures to mitigate effects of radiation exposure and prevent calamitous death rates caused by
accidental (Japan’s nuclear reactors) or intentional nuclear event. TP508 is an investigational drug which
has been shown to mitigate effects of whole body nuclear radiation (9Gy) in mice, and reduce
mortality/morbidity in irradiated mice. TP508 treatment post-exposure delayed mortality of mice exposed
to lethal doses of radiation (12Gy), and prevented radiation-induced apoptosis. Since radiation
significantly damages the intestines, we examined if TP508 exerted protective effects on
stemness/phenotype of intestinal crypts, which may contribute to the previously observed reduction in
mortality of irradiated mice treated with TP508. CD-1 (ICR) mice were exposed to whole body gamma
radiation (9Gy), or no radiation, followed by treatment of saline or TP508, 24 hrs post-irradiation. Mice
were euthanized 48hrs and 9 days post-exposure and colonic crypts were isolated and analyzed for their
length and architecture. Colons were processed for immunofluorescence and Western blot analysis for
stem cell populations expressing DCLK1, LGR5 and CD44 and examined for their proliferative/apoptotic
potential using PCNA/EdU and activated caspase-3 markers. Results demonstrated that lengths of colonic
crypts were significantly decreased in irradiated versus non-irradiated mice and treatment with TP508
reversed deleterious effects of irradiation on the morphology and colonic crypts lengths. Western blot
analysis for the indicated stem cell markers, strongly suggested that TP508 effectively protects against the
loss of stem cell populations in the colonic crypts of irradiated mice and increases proliferation. These
findings suggest that TP508 may protect stem cell populations from deleterious effects of irradiation, and
thus contribute towards reversing the damaging effects of irradiation on length/morphology of colonic
crypts by stimulating proliferation and decreasing apoptosis in crypts. We postulate that TP508 can be
developed as an effective novel drug for mitigation effects of radiation exposure.
(PS7-23) Endothelial cell responses in the hippocampus and cerebellum after irradiation to the young
1
2
3
2
mouse brain. Martina Boström ; Marie Kalm ; Thomas Björk-Eriksson ; Nina Hellström Erkenstam ; and
1
4
Klas Blomgren , Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden ; Institute
2
of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden ; Department of
3
Radiation Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden ; and Department of Women´s
4
and Children´s Health, Karolinska Institute, Stockholm, Sweden
Cranial radiotherapy is essential in the treatment of malignant pediatric brain tumors, but it is
associated with long-term side effects, including cognitive decline, particularly in children. The underlying
cellular mechanisms are only partly known and the relative contribution of, for example, reduced
neurogenesis, perturbed myelination, astrogliosis, neuronal cell death, and vascular dysfunction, is a
matter of debate. In the current study we investigated the role the vasculature in cranial radiotherapy.
Postnatal day 14 mice received a single absorbed dose of 10 Gy whole brain irradiation (IR) and were
sacrificed 6 hours, 24 hours or 7 days post IR. Endothelial cells were isolated from the hippocampus and
from the cerebellum using fluorescence-activated cell sorting, followed by cell cycle analysis and gene
363 | P a g e
