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The Andrew Marks Laboratory

The Marks lab is devoted to improving basic understandings of mechanisms that regulate calcium dependent signals including muscle contraction and cell growth. In particular the lab focuses on the structure/function relationships of ion channel macromolecular complexes including the ryanodine receptor/ calcium release channel (RyR) and the IP3 receptor. The lab employs a wide range of techniques including molecular and cell biology, confocal calcium imaging, structural biology, muscle physiology, and generates genetically altered animal models of human diseases to test hypotheses. Applications are welcomed from highly motivated students and postdoctoral fellows who should email arm42@columbia.edu and send a CV, statement of research interests and three letters of reference.

As a basic scientist and a physician, Andrew Marks, M.D., a cardiologist, chairman of the physiology department, and Founding Director of Wu Center for Molecular Cardiology, looks for ways to turn observations from the clinic or lab into new therapies for patients. This approach is responsible for the first drug eluting stent used to prevent coronary artery stent restenosis, and for a first-of-its-kind treatment for heart failure.

The research on heart failure and sudden cardiac death began with a clinical observation: the body's "fight or flight" nervous system is active at all times in heart failure patients - not just during times of stress - a condition that puts constant pressure on the heart. In the lab, Dr. Marks found that the constant stimulation of the heart alters the function of the calcium channel that controls the heart beat and strength of contraction of the heart. In heart failure, the channel starts leaking calcium, which can weaken the heart's pumping action and sets up the potentially fatal arrhythmias that are responsible for half of all deaths from heart failure.

Andrew Marks and his team found that a leak in RyR channel in the heart causes heart failure and cardiac arrhythmias - and have synthesized novel compounds called "calcium channel stabilizers" that fix the leak and prevent heart failure and arrhythmias in animal models. These novel therapeutics are being developed for testing in patients.
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The Marks laboratory in collaboration with the labs of Wayne Hendrickson and Joachim Frank works on the structure of ryanodine receptors. Our most recent advance has been the report of the high resolution structure of the type 1 ryanodine receptor solved by single-particle electron cryomicroscopy at an overall resolution of 4.8A°. The cytosolic assembly is built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by calcium.

 

 



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CUMC • The Marks Laboratory • Russ Berrie Medical Science Pavilion • 1150 St. Nicholas Avenue N.Y., N.Y. 10032