Presentation Title

Using Fluorescence Microscopy to Identify a Potential New Treatment for Heart Failure

Location

Reed 330

Start Date

20-4-2017 6:40 PM

Description

Cardiac glycosides have been used to treat heart failure for centuries, but they have a narrow therapeutic window, as they inhibit their target receptor nearly irreversibly. Overdoses can lead to arrhythmias. Phospholemman is a natural inhibitor of the same target as cardiac glycosides. It is possible that mutating phospholemman could achieve the same therapeutic benefit, while allowing cells to reverse the inhibition and thereby avoid an arrhythmia. I used fluorescence microscopy to screen candidate phospholemman mutants and identify one that binds more avidly to its target than the naturally occurring phospholemman. This mutant, L30A, caused similar effects as cardiac glycosides in rabbit heart muscle cells. Yet the effects were also reversed with stimulation of beta-adrenergic receptors, indicating that cells may be able to dynamically attenuate the effect and prevent an arrhythmia. This suggests that L30A phospholemman, used in a gene therapy approach to treating heart failure, could potentially outperform cardiac glycosides with a broader therapeutic window.

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Apr 20th, 6:40 PM

Using Fluorescence Microscopy to Identify a Potential New Treatment for Heart Failure

Reed 330

Cardiac glycosides have been used to treat heart failure for centuries, but they have a narrow therapeutic window, as they inhibit their target receptor nearly irreversibly. Overdoses can lead to arrhythmias. Phospholemman is a natural inhibitor of the same target as cardiac glycosides. It is possible that mutating phospholemman could achieve the same therapeutic benefit, while allowing cells to reverse the inhibition and thereby avoid an arrhythmia. I used fluorescence microscopy to screen candidate phospholemman mutants and identify one that binds more avidly to its target than the naturally occurring phospholemman. This mutant, L30A, caused similar effects as cardiac glycosides in rabbit heart muscle cells. Yet the effects were also reversed with stimulation of beta-adrenergic receptors, indicating that cells may be able to dynamically attenuate the effect and prevent an arrhythmia. This suggests that L30A phospholemman, used in a gene therapy approach to treating heart failure, could potentially outperform cardiac glycosides with a broader therapeutic window.