The goal of my
research program is the elucidation, at the molecular level, of
the signal transduction and gene regulatory events that underlie
the development of cardiovascular pathophysiology. Our approach
involves the development and utilization of transgenic and gene
targeted mice to perturb specific gene regulatory and signal transduction
cascades in the heart. This allows us to relate changes in the
action of single gene products with specific alterations of cardiac
biochemistry, physiology and pathophysiology in vivo.
The focus
of the current research in the laboratory is the role played by
cytokines, especially TNF-a, and the downstream transcription
factor NF-kB in ischemia/reperfusion (I/R) injury, cardiac hypertrophy
and heart failure. TNF-a and NF-kB are both involved in the cardiac
response to ischemia, and we have shown that genetic ablation
(TNF-a) or blockade (NF-kB) of both reduces the extent of myocardial
infarction after I/R. We are currently developing reagents for
acute blockade of NF-kB.
Similarly,
both TNF-a and NF-kB are activated during the development of cardiac
hypertrophy in several different murine models that exhibit concentric
cardiac hypertrophy, dilated cardiomyopathy and heart failure.
It is well known that TNF-a is upregulated in patients with heart
failure, but the cause and effect relationship between these factors
and specific cardiac pathophysiology is currently a matter of
great debate. We are employing unique transgenic mouse strains
that block the action of these molecules to conclusively determine
their roles in cardiac The hope is that understanding the mechanisms
of pathophysiology at the molecular level will facilitate the
development of novel pharmacological and/or gene therapeutic strategies
to fight heart disease.
Jones
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