BApps - University of Queensland, Brisbane, Australia - 2001
PhD - Biological Sciences, University of Queensland Brisbane, Australia - 2005
Myocardial remodeling refers to alterations in the cellular and extracellular components of the heart. Myocardial remodeling occurs as a result of adverse stimuli such as pressure overload (e.g. hypertension, aortic stenosis), volume overload (e.g. mitral regurgitation) or injury (e.g. myocardial infarction). My laboratory has two main areas of interests relating to the underlying mechanisms leading to adverse myocardial remodeling and ultimately heart failure: 1) the role of sensory nerves in mediating adverse myocardial remodeling; and 2) the mechanisms by which cardiac mast cells interact with other inflammatory cells and cardiac fibroblasts to regulate myocardial remodeling.
Sensory nerves are traditionally considered as having afferent functions, such as nociception, where they sense and transmit peripheral signals to the central nervous system. However, a new paradigm has emerged in which sensory nerves also exert efferent actions, allowing them to regulate function at the local tissue level. This is achieved through release of neuropeptides such as substance P, neurokinin A and calcitonin gene-related peptide. Recently, it has come to light that these afferent actions of sensory nerves may play a role in mediating adverse remodeling of the heart. My laboratory is investigating whether sensory nerves play a role in myocardial remodeling and heart failure induced by hypertension. We have evidence to show that sensory nerve neuropeptides may have dual roles with substance P being detrimental and calcitonin gene-related peptide protective. Currently, we are seeking to determine the mechanisms involved including the direct effects of these neuropeptides on cardiac fibroblasts, as well as how they regulate inflammation in the heart.
We and others have shown that cardiac mast cells are important in many pathologies of the heart. We have demonstrated specifically that in the hypertensive heart mast cells drive fibrosis through multiple mechanisms, including direct effects on cardiac fibroblasts, recruitment of other inflammatory cells, and regulation of specific cytokines. We have identified that mast cells stimulate cardiac fibroblasts to take on a myofibroblast phenotype and secrete collagen via tryptase activation of protease activated receptor-2. This in turn induces selective activation of the ERK 1/2 MAP kinase pathway, but not p38 or JNK MAP kinases. Currently, we are seeking to determine if other mast cell products (e.g. chymase) also activate cardiac fibroblasts. We are also interested in determining the mechanisms by which mast cells recruit other inflammatory cells (e.g. macrophages, T cells) into the heart and how this collective mix of inflammatory cells contribute to remodeling in the hypertensive heart.
Ultimately, we believe that it may be the collective actions of sensory nerves activating inflammatory cells that lead to cardiac fibroblast conversion to the active myofibroblast phenotype and fibrosis.
My laboratory uses rats and mice to investigate these sensory nerve-inflammatory cell interactions. In addition to whole animal studies, we also utilize isolated cardiac inflammatory cells, cultured dorsal root ganglia and isolated cardiac fibroblasts to determine the mechanisms by which sensory nerves and inflammatory cells direct the adverse myocardial remodeling process.