Calcium
Homeostasis and Cardiac Muscle Contractility
Heart failure is the single leading cause of death and the only
disease that is increasing in incidence and prevalence with an
overall five-year mortality rate of 50%. Current pharmacological
treatment of this devastating condition focuses on symptoms rather
than the underlying cellular mechanisms responsible for weakness
of the heart muscle. Cellular hallmarks of cardiac failure include
marked ventricular hypertrophy or dilation and abnormal cytosolic
calcium handling, associated with impaired contractility. The
overall goal of our research program is to elucidate the regulatory
mechanisms and signaling pathways underlying calcium homeostasis
in cardiac muscle and the alterations in these pathways underlying
the heart failure phenotype. Our current approach is to use Molecular
Genetics and generate mouse models, with alterations in the expression
levels of key Ca-handling proteins to determine their physiological
and pathophysiological significance in vivo. These genetically
altered models are characterized at the molecular, biochemical
and physiological levels, using state of the art techniques, including
Genomics, Proteomics and Bioinformatics.
Sarcoplasmic Reticulum Proteins Regulating Calcium Handling
We have specifically focused on sarcoplasmic reticulum, an internal
membrane system in muscle, which acts as a calcium source during
contraction and a calcium sink during relaxation. The findings
in our basic studies are extended to the Clinical Arena and the
expression levels or activity of the sarcoplasmic reticulum Ca-handling
proteins in failing human hearts are correlated with the depressed
cardiac function. Furthermore, the human genes encoding these
key calcium handling proteins are examined for the presence of
specific mutations, which may be associated with heart failure.
Our long-term goal is to build a comprehensive understanding of
the sarcoplasmic reticulum role in calcium handling mechanisms
that impact on control of muscle function in health and disease.
Publications
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