About Our Lab
Cardiac sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) actively transports Ca(2+) into the SR and regulates cytosolic Ca(2+) concentration, SR Ca(2+) load, and the rate of contraction and relaxation of the heart. Several studies have shown that altered SERCA pump activity contribute to the decreased SR Ca(2+) content and cardiac dysfunction during pathogenesis. In the heart, SERCA pump activity is regulated by two small molecular weight proteins, namely phospholamban and sarcolipin (SLN). The role of phospholamban in cardiac SERCA regulation is well established. On the other hand, the role of sarcolipin in SERCA function and cardiac contractility is poorly studied. The major focus of our research is to understand the role of sarcolipin in cardiac SERCA regulation and its importance during cardiac patho-physiology.
Ongoing research projects:
- We are using genetically engineered mouse models to determine the significance of sarcolipin downregulation in atria of patients with atrial fibrillation and heart failure. We hypothesize that loss of sarcolipin function enhances the SERCA pump activity in atria results in abnormal intracellular calcium handling and subsequent atrial remodeling, which cause atrial arrhythmias.
- The function of sarcolipin is modulated by CaMKII mediated phosphorylation of threonine 5 at the N-terminus. Transgenic mice expressing phosphorylation defective mutant sarcolipin results in bi-atrial enlargement and atrial fibrillation. This mouse model mimics many aspects of atrial pathology associated with human atrial fibrillation. We are studying the molecular mechanisms associated with atrial pathology in this mouse model. These studies may identify the molecular target(s) which initiates atrial pathology.
- We have identified a novel sarcolipin mutation in the atrial tissue of a human fetal atrial standstill. We are currently studying the structure-function relation of this mutation in sarcolipin function and its role in atrial pathology.
- The ubiquitin-proteasome system (UPS) plays an important role in cardiac remodeling in pressure-overloaded cardiac hypertrophy and in ischemic reperfusion injuries. However, the role of UPS in atrial fibrillation is yet to be studied. One of the major focuses of our research is to determine the role of UPS activation in atrial remodeling during cardiac pathology.