| The long-term
goal of our research is to develop treatments
for bronchioloalveolar carcinoma (BAC) and other
lung cancers. To understand how to cure these
diseases, we need to understand their biology.
BAC patients constitute about 5% of the total
lung cancer patients in the U.S. today; thus relatively
little research has been dedicated to the understanding
of the biology of this cancer, and even less into
finding a cure. In fact, researchers lack even
basic research models and tools to study this
disease. The goal of this proposal is to adapt
our mouse model of lung cancer to study BAC and
to gain insight into the biology of the disease
by looking at two of the proteins we believe are
involved. These proteins, BRM and BRG1, are part
of a large protein complex, called SWI/SNF, which
is known to be involved in regulating many cellular
processes, including the growth of cells. Our
research indicates that when SWI/SNF stops functioning,
the cellular processes it regulates are drastically
affected. In particular, cells can grow continuously
in the absence of these regulatory proteins. Our
laboratory has found that when the SWI/SNF components
BRM and BRG1 stop functioning, they affect the
ability of the regulatory protein Retinoid Acid
Receptor (RAR) to do its work and stop excessive
cell growth. Fortunately, we have also found that
it is possible to restore the function of BRM.
This suggests that BRM—and perhaps other
components of SWI/SNF—could help slow, or
stop, the growth of cancer-related cells, since
restoring BRM’s function would also restore
the function of RAR. To achieve this goal, we
need to define exactly which components of SWI/SNF
are affected in BAC and then determine how these
alterations affect RAR. We will use two main approaches:
first, we will identify specific genes involved
in BAC, and second, we will induce lung cancer
in our mouse model to see how RAR function is
changed when BRM and other subunits are removed.
We believe this research will benefit BAC patients,
not only by providing a means of understanding
the biology of this disease, but also by giving
us important insight into possible treatments.
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