Research

Specific ongoing/previous research projects



1. Regulation of cardiac function at the molecular level and analysis of signalling pathways in animal models and patients with heart failure

Our research program in Molecular Biology of Cardiac Muscle emphasizes the elucidation of calcium-handling proteins and signalling pathways in the regulation of cardiac function under physiological and pathophysiological conditions. Integrative approaches, utilizing methodology at the sub-cellular, cellular, organ and intact animal levels are applied. Special emphasis is placed on uncovering the "cross talk" between impairment of calcium homeostasis and cardiac remodelling, as it relates to the onset of hypertrophy and its transition to heart failure. The application of Genomics / Proteomics / Bioinformatics in these projects is of fundamental importance and we have already generated exciting new findings along these lines. These studies are coupled with parallel endeavors in cell-free systems, to evaluate the application of specific molecules in future "gene therapy" applications. We have established collaborations with Clinicians / Cardiologists to determine the Clinical relevance of our findings and uncover naturally occurring genetic variations in the key cellular players, identified in our animal models, which may contribute to the onset or progression of human heart disease.




Figure 1: Mutation screening analysis is performed in cardiomyopathy patients to identify novel genetic variations implicated in disease pathogenesis.   

2. Elucidation of the regulatory mechanisms and signalling pathways underlying calcium homeostasis and the control of contractility in the mammalian cardiac and skeletal muscles

Our current approach is to use Molecular Genetics and generate mouse models, with alterations in the expression levels of key Ca-handling proteins to determine their physiological significance in vivo. These genetically altered models are characterized at the Molecular, Biochemical and Physiological levels, using state of the art techniques. We have specifically focused on sarcoplasmic reticulum (SR), an internal membrane system in muscle, which acts as a calcium source during contraction and calcium sink during relaxation. The findings in our basic studies are extended to the Clinical Arena and the expression levels or activity of the sarcoplasmic reticulum Ca-handling proteins in failing human hearts are correlated with the depressed cardiac function. Our goal is to build a comprehensive understanding of the sarcoplasmic reticulum role in calcium handling mechanisms that impact on control of muscle function in health and disease.


Figure 2: Regulation of calcium homeostasis is mediated through the activity of a number of key sarcoplasmic reticulum (SR) proteins that affect muscle contractility and cardiac function.



3. Molecular identification and functional characterization of the internal membrane systems and structural components in skeletal and cardiac muscle

This is imperative for understanding how striated muscle cells develop and maintain their structural and functional integrity during repeating cycles of contraction and relaxation. Furthermore, the highly dynamic field of muscle cytoskeleton organization is another area of active research. Elucidation of the fundamental biology and pathophysiology of muscle cytoskeleton will give us a better insight on the etiologies that underlie severe muscular dystrophies and cardiac disorders. This will ultimately facilitate the development of innovative therapeutic strategies that may offer a potential avenue for treatment.

Figure 3: Determination of the subcellular localization of MLP through immunofluorescence analysis in skeletal muscle tissue sections.



4. Elucidation of the molecular mechanisms disturbed in cardiac and skeletal myopathies

Our goal is to decipher the molecular pathways involved in myopathies and cardiomyopathies in order to improve disease classification, diagnosis and therapy. It is of particular interest to determine how the molecular pathways of different skeletal and cardiac muscles are affected and how they compare in health and disease. The lessons to be learned could point to molecular mechanisms of high therapeutic value. The key tools will be global gene expression analysis in conjunction with extensive bioinformatical, molecular and proteomic work. For this purpose a number of animal models and human specimens are being used.




Collaborations

Our laboratory has ongoing collaborations with various labs in Europe, USA and Australia, providing complementary approaches to our research projects.




Laboratory Facilities

Microarrays - for whole genome gene expression profiling

Langendorff system - for ex vivo heart physiology studies

PTI (Photon Technology international) system - for intracellular ion transient measurements