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Exposure
of the human body to low doses of ionizing radiation in every
day life is unavoidable and is modified by our everyday activities
such as air travel, the location and make up of our homes,
X-rays and radiation therapy for diseases (such as cancer).
It is, thus, important that we understand the influence of
genetic background on cancer induction by low doses and low
dose rate radiation exposure.
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Explore
the molecular stress responses of both normal and
cancer cells following exposure to low dose or dose-rates
radiation.
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Evaluate how normal cells, exposed to radiation or
other DNA-altering agents, are changed to produce
cancer cells.
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Understand the interaction between the recently discovered
protein called clusterin and the p53 tumor suppressor
protein during the formation of cancer cells from
normal cells.
Clusterin
is dramatically expressed and secreted from human cancer
cells, but not from normal cells following very low doses
of radiation (0.02 Gy). Furthermore, cancer cells express
higher levels of clusterin because the p53 tumor suppressor
protein normally suppresses expression of this protective
factor. . When cells loose the ability to express normal
p53 levels, they are more prone to become cancerous. In
fact, the p53 tumor suppressor protein is lost in nearly
50% of all cancer cells. The p53 tumor suppressor protein
also controls how cells respond to radiation exposure
by increasing the time that cells have to repair damage.
Since tumor cells commonly loose p53 function, they over-express
clusterin after radiation exposures. Our laboratory is
investigating the effect of over-expressed secreted human
clusterin on tumor cells responses before and after exposure
to radiation. We are also exploring the use of secreted
clusterin as a marker of cancer as well as a marker of
radiation dose. The p53 also controls the ability of the
human body to eliminate badly damaged cells through programmed
cell death or apoptosis. It has been noted that secretion
of human clusterin protein by cancer cells results in
protection of neighboring cells from additional exposure
to low doses of radiation. This may contribute to "bystander
effects" observed in non-hit cells following radiation.
Our data suggest that monitoring blood serum levels of
clusterin may be an effective biodosimeter, telling a
person that they have been exposed to low levels of radiation.
We are exploring ways to monitor and reduce levels of
secretory clusterin. Reducing the level of clusterin will
prevent it from protecting tumor cells from apoptosis.
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Our
research hopes that by modifying and controlling the
level of clusterin it will be possible to increase
the effectiveness of tumor radiotherapy.
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Additionally, this research is training bright young
scientists for a career in molecular radiation biology,
cancer biology and genetics, thus assuring our continued
excellence in research to determine the health effects
and potential risk from exposure to low doses of radiation.
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