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Our
research focuses on understanding the regulation of the vascular
smooth muscle response and the vessel wall remodeling response
to injury. Atherosclerosis and the restenosis that complicates
interventions for arterial disease are problematic and poorly
understood. Vascular smooth muscle cell proliferation and
migration appear integral to the observed pathology, as is
the role of cell death. We are using several strategies to
understand the regulation of vessel wall biology, to alter
that biology and to control the vessel wall response to injury
and remodeling in vivo.
Basic fibroblast growth factor has been
shown to play a significant role in the arterial wall response
to injury. We are using gene transfer techniques to manipulate
the vessel wall cells at a molecular level in order to answer
questions about the biology of the vessel wall and also to
control the vessel wall response to injury. We use adenoviral
mediated gene transfer, and we use cell and organ culture,
and mouse, rat and rabbit models of arterial injury in addition
to a rabbit model of vein graft adaptation to the arterial
circulation. In addition to the animal work with histology
and electron microscopy, we study smooth muscle proliferation,
migration and apoptosis. We examine gene expression including
growth factor expression at the protein level with western
analysis and immunohistochemistry. We also study with northern
analysis and polymerase chain reaction the expression of RNA.
The effects of interruption of bFGF signaling with gene transfer
have been dramatic. We have observed excellent responses to
downregulation of bFGF signaling using adenoviral vectors
encoding antisense bFGF and vectors encoding a dominant negative
FGF receptor. We are continuing to dissect out the role of
bFGF in vivo.
We are also using similar models, assays
and methods to examine the role of hyperthermia and heat shock
proteins in the vessel wall. We have found significant amelioration
of the wall response to injury with induction of heat shock
with hyperthermia and also with adenoviral-mediated heat shock
protein 70i gene transfer.
Another regulator of smooth muscle growth
and function is uteroglobin, also called clara cell protein.
It is a multifunctional protein that has effects on platelets
and smooth muscle and also acts as an inhibitor of inflammation.
Overexpression of uteroglobin in the arterial wall confers
protection against the effects of arterial injury, and we
are currently using similar models and methods as described
above to study this mechanism.
Research fellows have presented at national
and regional meetings and won awards. Among others, the laboratory
has received research funding from The American Heart Association,
Foundations, the VA Merit Review and NHLBI-NIH RO1, and is
currently funded through 2006.
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