Research Areas
Joshua Goldhaber, MD, leads the National Institutes of Health-supported Goldhaber Laboratory that studies the basic science of heart muscle contraction and cardiac pacemaker cell function with a special emphasis on understanding how the strength of heart muscle is regulated at the cellular and molecular levels (excitation-contraction coupling). The overarching goal is to find ways to help diseased heart muscle perform beyond expectations.
Heart Failure With Reduced Ejection Fraction
From Goldhaber and Hamilton, Circulation, 2010.
Over the past two decades, the Goldhaber Laboratory has shown that the fundamental mechanism of heart muscle contraction, known as excitation-contraction coupling, fails as a result of the metabolic and oxidative stress typically seen in heart failure with reduced ejection fraction (HFrEF). Localized calcium release sites responsible for activating contraction, known as couplons, fail to activate normally 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 calcium signaling.
Heart Failure With Preserved Ejection Fraction
Half of all heart failure is caused by HFpEF. The underlying heart muscle abnormality is also associated with abnormal calcium cycling, but is quite different from what we have found in HFrEF. This likely explains why HFrEF therapies do not work in HFpEF. Understanding the basic mechanisms of HFpEF more thoroughly will allow us to develop specific treatments that actually improve symptoms and survival.
Understanding the Heart’s Pacemaker
The Goldhaber Laboratory has a particular interest in a cellular transporter known as the sodium-calcium exchange (NCX). The lab uses a suite of mice genetically modified to either overexpress, mutate or ablate NCX 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 is also a critical component of the heart’s pacemaker and conduction system. Mice without NCX have a characteristically abnormal heart rhythm and cellular studies reveal failure of normal pacemaker activity linked to defective cellular calcium handling.
From Cingolani E, Goldhaber JI, Marbán E. Next-generation pacemakers: from small devices to biological pacemakers. Nat Rev Cardiol. 2018 Mar;15(3):139-150.
Reagents and Resources
- Leica SP5 laser scanning confocal microscope specially outfitted with Molecular Devices, Inc. Axopatch patch clamp and bridge clamp setups as well as custom-designed perfusion and laser synchronization systems
- Two custom patch clamp setups outfitted with epifluorescence and IonOptix dual ratiometric photometry and active sarcomere shortening
- SciMedia MiCAM Optical mapping system for rodents
- Broad array of molecular biology and biochemistry equipment
- Cardiac cell isolation facility
- High-performance computers for image analysis
Contact the Goldhaber Lab
8700 Beverly Blvd.
Davis Building, Room 2058
Los Angeles, CA 90048