Fig. 1. A state of art set-up for simultaneous patch clamp recording and 2-D single cell Ca2+ imaging in Dr.Xie’s lab.
Dr. Xie’s research focuses on electrophysiology and Ca2+ handling in the heart, with particular
emphasis on the mechanisms underlying cardiac arrhythmias in experimental and natural animal models.
The following techniques are used in the studies: patch clamp, 2-D single cell Ca2+ imaging, Ca2+ spark
measurement, single cell contraction, intact tissue or whole-heart voltage and Ca optical mapping, and
monophasic action potential recording, etc. The studies in Dr. Xie’s lab are currently supported by a
NIH/NHLBI R01 grant (HL97979).
The specific research topics in Dr. Xie’s lab are:
1) Ionic and Cellular Mechanisms for Afterdepolarizations and Triggered Arrhythmias:
Fig. 2. Simultaneous recording of action potential (AP), Calcium transients (FCa) and pseudo-linescan in a single myocyte isolated form rabbit ventricle. A: control; B: under Ca2+ overload condition. Afterdepolarization and spontaneous Ca2+ wave are shown
Cardiac arrhythmias are disturbances of the normal electrical rhythm of the heart, usually due
to abnormal electrical activity in the heart. Severe arrhythmias, particularly self-sustained arrhythmias such as ventricular tachycardia or fibrillation (VT/VF), are a major cause of sudden cardiac death. Afterdepolarizations and triggered activities play essential roles in the genesis of the clinical arrhythmias. One of Dr. Xie’s projects is to explore the ionic and cellular mechanism(s) underlying afterdepolarizations and triggered activities in cardiac cells isolated from various animals. For example, the role of transient outward current (Ito) in the generation of early afterdepolarization (EAD) are currently investigated.
2) Cardiac Arrhythmias Induced by Oxidative Stress and Antiarrhythmic Mechanisms in Hibernating Animals:
Fig. 3. Effects of H2O2 on membrane currents and Cai cycling proteins in ventricular myocytes and induction of early afterdepolarization.
Reactive oxygen species (ROS) are generated as natural byproducts of normal oxygen metabolism and play important roles in cell signaling. However, under pathological conditions, such as heart failure and ischemia-reperfusion, ROS levels can become elevated and predispose the heart to arrhythmias via activation of Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII). The involvement of this signaling pathway in the antiarrhythmic mechanisms in a true hibernating animal (woodchuck) will be evaluated in Dr. Xie’s lab.
3) Regulation of Ca Spontaneous Release and Ca Waves:
Sarcoplasmic reticulum (SR) Ca spontaneous release and intracellular Ca2+ waves have been implicated in cardiac arrhythmogenesis under Ca2+ overload condition. However, it remains to be elucidated how the Ca2+ waves are regulated by other cellular factors. For example, recent studies have shown that mitochondria play important roles in Ca2+ homeostasis of cardiac myocytes. However, it is still unclear if mitochondrial Ca2+ flux can regulate the generation of Ca2+ waves and triggered activities in cardiomyocytes. In this project, Dr. Xie’s lab will study whether mitochondrial Ca2+ release and uptake can control the local Ca2+ level in the micro-domain near SR ryanodine receptors and plays an important role in regulation of intracellular Ca2+ waves and arrhythmogenesis. The effects of other Ca2+ pathways will also be evaluated.
4) Electrophysiological and Ca Handling Remodeling in Genetically Modified Animal Models or Cultured Single Cells:
The changes in electrophysiological and Ca handing properties and propensity to arrhythmogenesis will be characterized in some interesting transgenic mouse models.
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