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Research in the Goldhaber Laboratory is directed toward a more complete understanding of the molecular basis of contractile dysfunction of heart muscle associated with acute myocardial infarction and systolic heart failure. The laboratory is also concerned with the consequences of heart failure on other organ systems, particularly the kidney, leading to cardiorenal syndrome and other lethal complications of heart failure.
Over the past two decades, the Goldhaber lab has shown that the fundamental mechanism of heart muscle contraction, known as excitation-contraction (EC) coupling, fails as a result of metabolic and oxidative stress. For example, localized calcium release sites responsible for activating contraction, known as couplons, begin to drop out during metabolic inhibition in a predictable fashion. This is caused by a reduction in the ability of single calcium channels in the cell membrane to open properly because of energy deprivation and abnormal signaling.
The laboratory has a particular interest in the role played by the sodium-calcium exchange (NCX) transporter in the fate of cardiac contractility during metabolic stress. Mice genetically modified to either overexpress or ablate NCX have enabled the laboratory to make paradigm shifting observations. For example, the lab has shown definitively that NCX ablation allows heart cells to resist ischemia and reperfusion injury, and to maintain normal excitation-contraction coupling. NCX also participates in the activation of calcium release and contraction rather than behaving as a passive participant, removing cellular calcium after each beat. Recent findings in the lab have shown that NCX is a critical component of the heart’s pacemaker system. Mice without NCX have a characteristically abnormal heart rhythm and cellular studies reveal failure of intracellular calcium movements and normal pacemaker activity.