We develop chemical tools to track essential biomolecules and second messengers in vivo. The ultimate aim is to apply the tools to visualize and track crucial small molecules and ions involved in regulation of essential life processes like cell signalling, autophagy, and neural activity. The modus operandi is to design and synthesize selective fluorescence and magnetic resonance imaging probes that can image target molecules in living systems.
Dynamic changes in molecular distributions regulate key decision making processes in biology. The ability to track and visualize the molecular players therefore becomes central to endeavors in deciphering both decision making processes in biology and pathways in molecular homeostasis. One of the biggest challenges in molecular imaging is to detect these dynamic changes in molecular levels and localizations in vivo. Hence, rapid, reversible detection techniques are required which entail tuning the sensor response to the biologically buffered concentration of the analyte. We use fundamental coordination chemistry and molecular recognition principles to incorporate turn-on and ratiometric sensing features into optical and magnetic resonance imaging probes such that the sensors give a selective reversible signal enhancement only the presence of the specific target molecule. Our group is particularly interested in developing sensors for metal ions implicated in neuro-degeneration, phospholipids in cell signaling, and autophagy markers including proton fluxes. The major challenge in all these systems is that the target molecules are not genetically encoded and hence have been previously tracked indirectly by using genetically modified fluorescent proteins. Detection specificity is low due to the interaction of the modified protein with multiple small molecules. The sensitivity suffers as well due to background signals from unbound proteins. To address these challenges we bring in reversible turn-on and ratiometric sensing features into small molecule, peptide, and protein-based probes. The ultimate success of a chemical strategy for molecular detection lies in the ability to utilize the designed chemical tools to track molecules in live biological systems. Therefore, optical and magnetic resonance imaging modalities are used to validate our probes for in vivo applications in molecular imaging.
An important end-point is to make the sensors widely applicable as chemical tools for elucidating fundamental biological mechanisms underlying cell-signaling and regulation. Toward this goal, the novel sensors have also been shared via collaboration and successfully applied in different biological model systems. Importantly, aberrant molecular concentrations are crucial determinants of diseased states in living systems. Our forays into sensor development have not only led to novel chemical probes but have also enhanced our understanding of chemical selectivity principles. Insights obtained from our fundamental sensor design endeavors have therefore also initiated newer applied directions in the development of strategies for early disease diagnosis and routes for targeted chelation therapy in our laboratory.