Research
GPCR-G protein pharmacology: A major area of research in our group aims to deliver a molecular picture of how subcellular signaling is regulated and develop optogenetic applications to achieve this goal and for in vivo applications. Specifically, we focus on (i) molecular regulation of G protein-coupled receptor (GPCR) and subtype-specificity-driven G protein subunit signaling, both at the cell surface and endomembranes, (ii) photochemistry of retinaldehyde in photoreceptor cells and its phototoxic effects on retina photo-damage, and (iii) the development of optogenetic tools for subcellular and in vivo regulation of signaling with user-defined spatial and millisecond to sub-second temporal control. Signaling circuits and cellular chemistry we study have major pathological significance because they are critical players in homeostasis. Since the GPCR-G protein pathways are major drug targets, we hope to deliver defective molecular processes in devastating conditions, including cancer, heart diseases, and neurological disorders. We also explore the molecular underpinnings and mitigation strategies of light-induced vision damage. We also utilize data-guided computational modeling to map signaling networks in silico and molecular dynamic simulations to design optogenetics tools with customized signaling selectivity and spectral properties.
Subcellular Optogenetics: I played a crucial role in opsin photopigment development for GPCR and G protein optogenetics. Continuing this, my group also explores the intricate spectral-signaling-photochemical properties of opsins in humans and the large-opsin-family members to (a) explain how they regulate cellular and behavioral responses and (b) engineer opsins with tailored properties for in vivo optogenetics. For instance, Opsin photopigments are evolved to sense light. Photons in the visible spectrum have the required energy to induce electron transitions in the opsin-bound chromophore retinal, causing retinal isomerization and subsequent massive conformational changes in the opsin protein to initiate light sensing in animals. By adjusting the amino acids in the retinal binding cavity, we alter the excitation energy requirements of the opsin, tuning their light sensing properties. Opsins are G protein-coupled receptors (GPCRs) in the receptors family that houses many GPCRs involved in health and disease, including adrenergic and opioid receptors. Since chemical ligands control these GPCRs, we engineer analogous light-controlled opsins to mimic and hijack chemical-controlled GPCR signaling for cellular and in vivo signaling interrogations.
Photophamacology: We aim developing tools and approaches to overcome the limitations of traditional pharmacotherapy. In this approach, the administration of a photoactive molecule is followed by the light irradiation of a precise subcellular, cellular, tissue, or organ location to activate, inhibit or modulate cellular function is sought. Spatial and temporal controllability of drug action could precisely control the intended biological function with significantly minimized off-target effects, including cytotoxicity and organ failure. Additionally, such a targeted drug action would mitigate the development of drug resistance. We employ structure-guided genetic-protein engineering to develop small-protein drug-like molecules and examine their ability to control signaling in unmodified cells on optical command. Our research team's steady track record shows consistent innovation and productivity.
Subcellular Optogenetics: I played a crucial role in opsin photopigment development for GPCR and G protein optogenetics. Continuing this, my group also explores the intricate spectral-signaling-photochemical properties of opsins in humans and the large-opsin-family members to (a) explain how they regulate cellular and behavioral responses and (b) engineer opsins with tailored properties for in vivo optogenetics. For instance, Opsin photopigments are evolved to sense light. Photons in the visible spectrum have the required energy to induce electron transitions in the opsin-bound chromophore retinal, causing retinal isomerization and subsequent massive conformational changes in the opsin protein to initiate light sensing in animals. By adjusting the amino acids in the retinal binding cavity, we alter the excitation energy requirements of the opsin, tuning their light sensing properties. Opsins are G protein-coupled receptors (GPCRs) in the receptors family that houses many GPCRs involved in health and disease, including adrenergic and opioid receptors. Since chemical ligands control these GPCRs, we engineer analogous light-controlled opsins to mimic and hijack chemical-controlled GPCR signaling for cellular and in vivo signaling interrogations.
Photophamacology: We aim developing tools and approaches to overcome the limitations of traditional pharmacotherapy. In this approach, the administration of a photoactive molecule is followed by the light irradiation of a precise subcellular, cellular, tissue, or organ location to activate, inhibit or modulate cellular function is sought. Spatial and temporal controllability of drug action could precisely control the intended biological function with significantly minimized off-target effects, including cytotoxicity and organ failure. Additionally, such a targeted drug action would mitigate the development of drug resistance. We employ structure-guided genetic-protein engineering to develop small-protein drug-like molecules and examine their ability to control signaling in unmodified cells on optical command. Our research team's steady track record shows consistent innovation and productivity.
Laboratory and instrumentation
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Genetic & molecular engineering to hijack cell signaling and behaviors using light!
Structure-based protein engineering, sensor designing and decoding chemistry of living cells
