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Projects
Heterozygous Nkx2-5 mutations cause a wide
variety of cardiac malformations in man. Curiously, the identical
mutation in different persons can result in different types of
defects or none at all. A large-scale genetic screen in our
laboratory has identified multiple modifier loci that influence
the incidence and types of heart defects found in Nkx2-5 mutant
animals. Other ongoing projects explore specific genetic and
molecular interactions to understand mechanisms of epistasis and
atrioventricular canal development.
The methods developed within the lab to diagnose cardiac
malformations in mouse embryos and neonates have in addition
permitted us to discover unsuspected roles for other genes in
cardiac development in collaboration with other laboratories.
Heterozygous mutations of Nkx2-5 are associated
with atrioventricular conduction defects in man and mouse. We
showed that the physiologic defects are related at least in part
to anatomic hypoplasia of the central and peripheral conduction
systems. We also found that a specific subdomain of the AV node
is absent in Nkx2-5 mutant animals. We therefore seek to
understand the mechanisms by which Nkx2-5 loss-of-function
mutations lead to a hypocellular conduction system and the
function of the missing subdomain of the AV node using
developmental and electrophysiologic methods.
Heart failure is associated with genome-wide
changes in gene expression, as determined by microarray
experiments. These changes represent the outputs of the
underlying pathophysiologic regulatory mechanisms. To elucidate
the transcriptional pathways that regulate gene expression in
normal, mutant and diseased states, we have taken a computational
approach to identify DNA sequence motifs in the promoters of genes
that may regulate their expression in the heart. These motifs,
which are then studied experimentally, may help to identify novel
strategies to treat heart failure or to provide general mechanisms
of diseases caused by transcription factor mutation.
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SCHOOL OF MEDICINE
