The Sarcoplasmic Reticulum (SR)

The sarcoplasmic reticulum (SR) is an internal membrane system in muscle and it has been implicated as a major contributor to the depressed function in heart failure. The SR acts as a calcium source during contraction and a calcium sink during relaxation. Relaxation is mediated by the transport of calcium into the sarcoplasmic reticulum lumen by a Ca-ATPase, which is under reversible regulation by phospholamban, a low molecular weight phosphoprotein. Calcium then binds to calsequestrin in the lumen of the SR. For the initiation of contraction, calcium is released through the calcium channels or ryanodine receptors, which are under regulation by junctin, triadin and partially by a novel protein, the histidine rich calcium-binding protein. Thus, the SR is the major regulator of Ca2+-handling and contractility in muscle (See Figure Below).

To elucidate the physiological significance of the key SR/Ca-regulatory proteins in vivo, we use Molecular Genetics to generate mouse models with alterations in the expression levels or the activity of each of these proteins. Our models are characterized at the Molecular, Biochemical and Physiological levels, using state of the art techniques, including Functional Genomics and Proteomics. This integrative approach reveals unique phenotypes, which provide significant insights into the key regulatory players in muscle and their role in health and disease. Furthermore, studies on: a) muscle development; b) aging; and c) development of hypertrophy with its transition to heart failure, or various myopathies in the mouse models, offer unique insights into the role of each of these calcium-handling proteins in muscle function. Identification of compensatory mechanisms, accompanying each gene alteration, also provides an in-depth understanding of the molecular communication pathways in muscle.

Our goal is to build a comprehensive understanding of the sarcoplasmic reticulum role in calcium handling mechanisms that impact on the control of muscle function in health and disease.

Our research team consists of 15-20 researchers, including 6-10 postdoctoral fellows, 4-6 Ph.D. students, 2-4 research assistants and several college students. We are also collaborating with several scientists and laboratories in the U.S., Canada, Europe and Japan in a concerted effort to build a comprehensive understanding of the calcium handling mechanisms that control muscle function and dysfunction.