My broad research interests are in the emerging areas of biomedical sciences such as system bioenergetics, phosphotransfer enzymes and networks, metabolomics, metabolic signaling circuits and metabolic sensors in health and disease:
Adenylate kinase biology, energetic and metabolic signaling role.
Since the discovery of adenylate kinase (AK) energy transfer shuttle and metabolic signal ligand conduction system a growing body of evidence indicate that AK system represents a major cellular metabolic monitoring hub. AK-mediated AMP signaling through metabolic enzymes and AMP-activated protein kinase (AMPK) is central to cell energetics, body energy sensing, developmental processes and regulation of diverse functions such as blood flow, appetite control and hibernation. Mutations in AK isoforms are associated with a number of human diseases.
Our studies have uncovered the significance of AK in energetics of muscle contraction, regulation of mitochondrial respiration, nuclear transport, metabolic signaling, coronary blood flow and cardioprotection. More recent studies are focused on the role of AK and AMP signaling in nuclear and cell cycle energetics, in stem cell cardiac differentiation, asymmetric cell division, tissue renewal and myocardial regeneration. We are applying system bioenergetics and metabolomics approaches to track and facilitate stem cell cardiac differentiation by dissecting the significance of metabolic circuits and mitochondrial networks in cardiogenesis and cardiac regeneration.
Our particular emphasis is on molecular mechanisms of AK and AMPK kinetic interaction and cytosolic-nuclear distribution in response to metabolic stress. Molecular mechanisms of AK translocation to cell nucleus during cell division cycle and energy support for mitotic spindle movement and cytokinesis are being addressed. Moreover, the significance of AK-catalyzed nucleotide dynamics in regulation of our discovered intracellular Mg2+ oscillations and waves is being elucidated.
Phosphotransfer networks, system bioenergetic and phosphometabolomics.
Our proposed phosphotransfer network concept integrating adenylate kinase, creatine kinase, and glycolytic/glycogenolytic energy transfer and signal communication systems provides a framework in modern system bioenergetics field. Abnormalities in the dynamics of cellular phosphotransfer networks, glycolytic and glycogen metabolism are associated with human diseases.
Our developed unique 18O-assisted 31P NMR and mass spectrometric phosphometabolomic technique allows simultaneous measurements of cellular phosphotransfer dynamics, ATP turnover, energetic signal communication between ATP consumption and ATP production sites and metabolic flux through adenylate kinase, creatine kinase, glycolytic and NDPK catalyzed reactions, knowledge of which is necessary for system biology approach.
Bioenergetics of failing hearts and cardioprotection.
This area stems from our pioneering studies revealing cumulative defects in different steps of heart energetic system, including phosphotransfer deficit, mitochondrial and metabolic signaling abnormalities leading to heart failure and that pluripotent vasopeptidase inhibitors can protect energetic enzymes.
Our studies are employing system bioenergetics approach and GC/MS, LC/MS and 18O-assisted 31P NMR metabolomic technologies to understand mechanisms of heart failure and cardiac resynchronization therapy.
We are further pursuing our novel concept in cardioprotection focused on enzyme protection. Using small molecule ligands, we are developing approaches to "shield" and protect critical energetic enzymes in ischemia-reperfusion and failing heart models. By protecting enzymes from oxidative and proteolytic damage we expect to reduce myocardial injury and prevent developing heart failure.