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.

Kranias Lab
Research Topics

Heart Failure

Cardiac Function

The Sarcoplasmic Reticulum

Phospholamban

SERCA

Calsequestrin

HRC

Junctin

HAX-1

Heat Shock Proteins

Protein Phosphate 1 Inhibitor-1

Proteomics & Phosphoproteomics

Transgenic Rabbits

Human SR Genetic Variations