Biomedical Engineering Reference
In-Depth Information
NF-
B is a central mediator of inflammatory responses to radiation exposure (Li and
Karin, 1998; Beetz et al., 2000; Linard et al., 2004), it was hypothesized that
downmodulating NF-
k
B activity by pharmacological means could be of benefit in
the radiation setting. As shown recently, this is indeed the case in zebrafish embryos
(Daroczi et al., 2009), inmice (Epperly et al., 2007), and in rats (Linard et al., 2004). In
all three species, a survival advantage was found by using different pharmacological
NF-
k
B is the relevant target for radiation protection is
underlined by the finding in zebrafish that multiple inhibitors of canonical NF-
k
B inhibitors. That NF-
k
B
activation were effective whereas several proteasome inhibitors including PS-341
(bortezomib) were not (Daroczi et al., 2009).
A similar argument can be made for GSK3 inhibitors, which were first tested
as radiation protectors in the cranial radiation setting (Thotala et al., 2008).
Recent unpublished work showed that a wide variety of GSK3 inhibitors with
different mechanisms of action afford radiation protection to zebrafish measured by
extended survival as well as improved gastrointestinal morphology and function
(Table 21.1). While it is presently unknown how attenuating GSK3 activity exerts
radioprotection, these results underline that it is likely that GSK3 is a relevant target
for radiation protection.
k
21.10 SUMMARY
During the past 20 years, the molecular mechanisms of the radiation and genotoxic
stress responses have been mapped in exquisite detail. While this work has revealed
complex, interconnected molecular networks, less has been learned about the
integration of these networks in vivo in tissues and organisms. As recognized by a
recent NCI workshop Stone et al., 2003, the tissue context is indispensable to
accurately gauge the functional importance of specific molecular events in the whole
organism consistent with the concept of emergent properties of complex systems. For
example, inflammatory processes rely on the interplay of multiple cell types rather
than homogeneous cell populations as studied in culture. Recent work has shown that
screening for radiation modulators in zebrafish is a promising tool to identify suitable
targets and select appropriate agents for pharmacological intervention. Effects of
ionizing radiation on both overall survival and organ function have been defined as
described inmore detail above. It has been shown that zebrafish embryos are protected
by known radiation protectors (ROS scavengers). In addition, pharmacological
modulation of NF-
B and of GSK3 signaling has been observed to radioprotect
both zebrafish and mice and this protection extends to the gastrointestinal system, a
radiosensitive organ site of high clinical relevance. An important advantage of using
zebrafish in studying radiation protectors is the capacity to rapidly test multiple agents
affecting a given pathway. This circumstance helps to distinguish the contribution of a
specific molecular target to radioprotection as opposed to off-target effects associated
with any individual agent. In addition, antisense techniques based on morpholino-
mediated inhibition of translation can be employed to further probe the contribution of
a given pathway or drug target in the radiation response. An example for the use of this
k
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