Research

We investigate the biology of matrix metalloproteinases (MMPs) in health and disease.

The past: For the past decade or so, we searched for new substrates of MMPs and mechanisms by which MMPs impact the cardiovascular system.

New stuff: Working with mice deficient in MMP-2 (Mmp2-/-), we have recently discovered a heart-centric endocrine mechanism which is inhibited by MMP-2 and mediated by a phospholipid hydrolase that we coined 'cardiac secreted phospholipase A2 (cardiac sPLA2)'. The molecular identity of cardiac sPLA2 is unknown. It may be a mixture of conventional sPLA2s or a completely novel enzyme. Contrary to our initial expectations, cardiac sPLA2 is not primarily PLA2G5 (which has historically been considered the major sPLA2 isoform in the heart). Cardiac sPLA2 is purportedly activated by chemokines – a hypothesis our laboratory is actively investigating. We think that cardiac sPLA2s is released from myocardium and acts on distal tissues (e.g., liver) as well as on the heart impacting their inflammatory and metabolic state.  

Significance of our findings: The discovery of cardiac sPLA2 and its key role in inflammation may help to understand the cardiovascular and systemic effects of MMP-2 inhibitor drugs, such as doxycycline – the only FDA approved MMP inhibitor. Moreover, our findings suggest a plausible disease mechanism for human MMP2 deficiency – a rare and relatively neglected inflammatory condition involving crippling arthritis and cardiac problems.

Techniques and scope of research: Our research combines biochemical, cell biological and integrative animal physiology studies and is relevant to a cluster of diseases including cardiac, metabolic and inflammatory diseases, including hypertrophic cardiomyopathies, hypertension, obesity, diabetes, and arthritis.

Training philosophy: We are a small laboratory where students are tasked with solving scientific problems for which there are no current answers at this time. Many of our research problems fall in the category of biomedical research. Our students are expected to conduct highly interdisciplinary research and to exhibit a high level of motivation as well as being able to team work.