Current research projects include:
Acquired long QT syndrome molecular mechanisms: The acquired long QT syndrome can be induced in susceptible patients exposed to a broad array of different drugs. This has been a long-standing area of investigation by Craig January. Recent investigations by January and investigators in his lab have revealed that the likely target of these drugs is the promiscuous potassium channel, HERG. For example, cellular electrophysiology studies revealed many of the early antihistamine medications, including the astemizole metabolites, desmethylastemizole and norastemizole, are potent HERG blockers that can lead to prolongation of the action potential and associated risk of ventricular arrhythmias. Current work focuses on defining structure-activity relationships governing drug-blockade of HERG channels.
Antiarrhythmic drug molecular interactions: Longstanding investigations by Jonathan Makielski have led to an important understanding of the mechanism of interaction of antiarrhythmic drugs with voltage-dependent sodium channels in the heart. This interaction is the basis of action for many of the currently effective antiarrhythmic drugs. Using molecular biology techniques and heterologous expression of designer channels, Makielski's laboratory is defining a detailed model of blockage of the sodium channel by the antiarrhythmic drug lidocaine.

Electrical remodeling in the failing heart: Investigations led by Jonathan Makielski have revealed a persistent inward Na current which contributes to the prolonged action potential in failing myocytes. The proarrhythmic effect of this current can contribute to the high risk of sudden death in patients with heart failure (HF). Studies are continuing to characterize this current and its regulation. Investigations from Dr. Kamp's lab have demonstrated that the L-type Ca2+ channels are half as abundant in failing myocytes from the canine tachycardia pacing model. In addition, currents through these channels decay more slowly, contributing to the prolonged action potential noted in HF. This loss of L-type Ca2+ channels contributes to the abnormalities of excitation-contraction coupling and contractile dysfunction.

Congenital long QT syndrome molecular mechanisms: Craig January, in collaboration with Gail Robertson, PhD (Physiology), have provided new key understandings of the molecular pathways by which mutations in the potassium channel gene, HERG, can lead to the long QT syndrome (LQT2), a disease manifested by potentially fatal ventricular arrhythmias often striking children and young adults. These investigations have demonstrated that defects in membrane trafficking of the mutant channels underlie the defect in repolarization of the cardiac action potential in many of the disease-producing mutations of HERG. In addition, January and Makielski have provided evidence for a new strategy to treat the long QT syndrome due to a mutation in the cardiac sodium channel (LQT3) using the antiarrhythmic drug flecainide.
Regulation and function of ATP-dependent potassium channel (KATP): The KATP channel plays an important role in the electrical function of the heart, especially in pathological conditions such as ischemia, ischemic preconditioning and diabetes. Jonathan Makielski's laboratory initially demonstrated the critical regulation of the KATP channel by membrane phospholipids. Current research is focused on defining the molecular pathways involved in this regulation using mutagenesis techniques as well as knockout mice.

Caveolae and cardiac hypertrophy: Moderate to severe cellular structural remodeling occurs in conditions of cardiac hypertrophy and congestive heart failure. Findings from Dr. Balijepalli's lab demonstrate that muscle specific caveolin, Caveolin-3, and cardiomyocyte caveolae regulate hypertrophic signaling in the ventricular mycytes. To understand the role of caveolae and Caveolin-3 in cardiac hypertrophy Balijepalli lab is employing cardiac specific conditional Cav-3 knockout and Cav-3 overexpression mice (in collaboration with Hemal Patel, PhD, USCD, San Diego, and Leanne Cribbs, PhD, Loyola University). A variety of research techniques are employed in these studies including proteomic approaches, fluorescence confocal imaging, FRET, electron microscopy and cellular electrophysiological (patch clamp).
Neurohormonal regulation of L-type Ca2+ channels: As the initial trigger for excitation-contraction coupling in the heart, the L-type Ca2+ channel is exquisitely regulated by many signaling pathways. A variety of neurohormones in the heart, including endothelin-1 and angiotensin II, lead to the activation of protein kinase C. Timothy Kamp's laboratory, in collaboration with Jeffrey Walker, PhD (Physiology) has recently demonstrated that activating protein kinase C by these neurohormones or photorelease of diacylglycerol, a protein kinase C activator, up-regulates the activity of L-type Ca2+ channels. Current efforts are defining the mechanisms involved in this up-regulation using molecular biology, cellular electrophysiology and transgenic mice with conditional knockout of subunits of the channel complex.
Human embryonic stem cell derived cardiomyocytes characterization and applications: Embryonic stem (ES) cells are pluripotent cells capable of developing into specific cell types of all three germ layers including cardiomyocytes. Timothy Kamp's laboratory in collaboration with James Thomson (Dept. of Anatomy) has succeeded in differentiating human ES cells into cardiomyocytes. Initial electrophysiological characterization of these hES-derived cardiomyocytes have revealed distinct cell types including embryonic atrial, embryonic ventricular and nodal. Ongoing research is focused on optimizing the differentiation of human ES cells into cardiomyocytes and characterization of the resulting cardiomyocytes. Ultimately, these cells will have tremendous potential for cell-based therapies for a variety of heart diseases and will provide a useful cell culture model for a variety of basic research studies.

Lamin A/C and Dilated Cardiomyopathy: Lamins A and C are filament proteins and key components of nuclear lamina, that provide structural support for the nucleus and to anchor chromatin and nuclear pores to nuclear envelope. Mutations in LMNA gene have been reported in a number of cardiac diseases with occurrence of cardiac complications of dilated cardiomyopathy with conduction defects and dysarrhythmias. Balijepalli lab, in collaboration with Timothy Hacker, PhD, is investigating on Lamin A/C (LMNA) mutations and dilated cardiomyopathy. Studies are being carried out utilizing LMNAN195K/N195K mice and employing gene microarrays, proteomic analysis approaches to identify alterations in the signaling pathways, while electron microscopy technique is used to study the structural abnormalities in the atrial and ventricular myocytes. These studies will help in understanding the pathophysiology of the dilated cardiomyopathy and mechanism of arrhythmia in these mutant mice.

CMARP Faculty
Craig T. January, MD, PhD, cellular electrophysiology, HERG potassium channels, long QT syndrome, Ca2+ channels
Timothy J. Kamp, MD, PhD, cellular electrophysiology, embryonic stem cells, excitation-contraction coupling, heart failure, Ca2+ channels, neurohormonal signaling, myocardial regeneration
Jonathan C. Makielski, MD, cellular electrophysiology, electrical remodeling, heart failure, Na channels, KATP channels
Ravi C. Balijepalli, PhD, caveolae and cardiac protection, cardiac hypertrophy, heart failure, electrical and structural remodeling, Ca2+  channels, cellular electrophysiology, electron microscopy and proteomics

Lee L Eckhardt, MD, cellular electrophysiology, mechanisms of arrhythmias, KATP channels, long QT syndrome