The candidate received his Ph.D. from the UC Berkeley, under the joint direction of Kenneth Raymond andRobert Bergman where he studied host-guest chemistry, molecular recognition, and catalysis in water-solublesupramolecular complexes. He is currently an NIH postdoctoral fellow in Stephen Lippard's laboratory at MITworking on developing fluorescent probes for nitric oxide. The candidate's research interests span the field ofmolecular recognition with a specific focus on how microscopic processes lead to the recognition of individualatoms, functional groups and molecules. The candidate will use his background in mechanistic studies andmolecular recognition to pursue his research interests as a principle investigator. His independent research willfocus on the development of new tools for the detection and imaging of small molecules in biology. Nitric oxide (NO) and hydrogen sulfide (H2S) are now accepted as biologically important gaseoustransmitters. Both NO and H2S are produced endogenously and are finely regulated by the body. Nitric oxide isbeneficial for vasodilation and immune activity at low cellular concentrations but overproduction can lead to theproliferation of reactive NO species that have been implicated in carcinogenesis and several degenerativeneurological disorders, including Alzheimer's (AD), Parkinson's, and Huntington's disease, as well as multiplesclerosis. Similarly, H2S has been implicated in AD, Downs syndrome and other forms of metal deficiency. H2Salso plays an active role in inflammation and in blood pressure regulation. Despite the recognized importanceof both of these gaseous transmitters, the current methods for detection in live cells are limited. The postdoctoral phase of the proposed research will focus on the development of new NO-selectivefluorescent probes that address current limitations of NO detection. Transition metal based NO binding siteswill be used to develop probes that can reversibly bind NO and probes that emit in the NIR. The proposedfamily of fluorescent probes will use paramagnetic (S=1/2) metals serving the dual role as both fluorescencequencher and NO binding site. Coordination of NO will form a diamagnetic (S=0) complex and restore thefluorescence of the pendant fluorophore. Adsorption or covalent attachment of such complexes to solubilizedsingle-walled carbon nanotubes (SWNTs) will be used to develop NO-selective probes that emit in the NIR. The independent research phase of the proposed research will investigate the design of H2S-selectivefluorescent probes for the imaging of endogenously produced H2S. Currently, such H2S detection methods arelacking and most measurements rely on bulk tissue measurements. The new H2S-selective fluorescent probesfor use in live cells will provide much needed tools for the study of the biological functions of H2S. The uniquephysical properties of H2S will all be exploited in the design of H2S-selective fluorescent probes. Fluorophoreswill be derivatized with specially designed protecting groups that can only be removed by H2S. Removal of thefluorophore protecting group will restore the fluorescence, thus forming a turn-on probe for H2S.
Both nitric oxide (NO) and hydrogen sulfide (H2S) have been identified as important endogenous gaseous transmitters in the human body and have been implicated in carcinogenesis, hypertension, and several neurological disorders including Alzheimer's disease, Parkinson's disease, Downs syndrome, and multiple sclerosis. Despite this interest, there are currently few methods to detect or image intracellular levels of these small molecule transmitters. This proposal presents the design of fluorescent probes for NO and H2S, which would allow for the selective detection and imaging of these endogenous gasses in live cells.
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