1988-1989 Assistant Research Scientist, Department of Ophthalmology, University of Florida, Gainesville, FL.
1990-1992 Assistant Scientist II, R.S. Dow Neurological Sciences Institute and Dept of Ophthalmology, Good Samaritan Hospital & Medical Center, Portland, OR.
1990-1992 Assistant Professor of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR.
1990-1992 Research Assistant Professor of Ophthalmology, Oregon Health Sciences University, Portland, OR.
1991-1992 Associate Scientist I, Robert S. Dow Neurological Sciences Institute, Good Samaritan Hospital and Medical Center, Portland, OR.
1992-1994 Assistant Professor, Department of Ophthalmology, Adjunct, Pharmacology; University of Washington, Seattle, WA.
1994-1997 Associate Professor of Ophthalmology, Adjunct, Pharmacology; University of Washington, Seattle, WA.
1997-2005 Professor of Ophthalmology, University of Washington, Seattle, WA.
1997-2005 Professor (Adjunct) of Pharmacology, University of Washington, Seattle, WA.
1998-2005 Professor (Joint) of Chemistry, University of Washington, Seattle, WA.
1999-2005 Research Affiliate, Regional Primate Research Center, University of Washington, Seattle, WA.
1999-2005 E.K. Bishop Professor, Department of Ophthalmology, University of Washington, Seattle, WA.
2005-2018 Professor and Chair, Department of Pharmacology, Case Western Reserve University, Cleveland, OH.
2005-2018 John H. Hord Professor, Department of Pharmacology, Case Western Reserve University, Cleveland, OH.
2019- Elected to the U.S. National Academy of Medicine
The light-sensing apparatus of the eye is found within the rods and cones—two types of specialized cells located in the posterior of the retina. Of the two types of receptors, rod cells exhibit greater light sensitivity (lower threshold) and a slower reaction time. Cone cells, on the other hand, respond rapidly, and provide greater discrimination of temporal, spatial, and spectral detail. The light signal captured by photoreceptor cells triggers a cascade of chemical reactions, called phototransduction, which ultimately generates a neuronal signal.
Like the rod cell, cone cell activation involves the photoisomerization of the 11-cis-retinal chromophore bound to an opsin-like transmembrane protein. In the case of the cone cell, however, there are three variants of the transmembrane protein. When bound to the chromophore, each of the resulting visual receptor pigments exhibit a characteristic red, blue, or green absorption maxima which leads ultimately to color vision. Recent work indicates that the differences in absorption maxima are a function of differences in amino acid sequences within each pigment. Similar analyses of structure, reactivity and function will have to be performed for all the critical receptors (GPCRs), catalysts and reaction terminators (arrestins, recoverins, guanylate cyclase activating proteins) within the cone cell phototransduction cycle. Light-triggered events initiated in rod and cone outer segments were the subject of numerous investigations during the last two decades, most notably using molecular approaches and electrophysiological measurements of the isolated retina or photoreceptor cells. The light events are intimately intertwined with the regeneration reactions that involve two cell systems. Every photon of light that triggers photoisomerization is counterbalanced by regeneration of rhodopsin with newly synthesized 11-cis-retinal. Contributions from numerous investigators have provided substantial advances in our fundamental knowledge of phototransduction and the regeneration of rhodopsin. These have included the identification of phototransduction and retinoid processing enzymes, cation channels, and retinoid-binding proteins in the retina-RPE system, as well as determination of the mechanisms of action of these proteins. Furthermore, within the past decade there has been substantial new information regarding the links between specific retinal diseases and identified abnormalities of the retinoid cycle.
Many unresolved issues relevant to phototransduction, light- and dark-adaptation, and the chemical processing of retinoid cycle intermediates remain unanswered, including the enzymology of the retinoid cycle, the mechanisms by which these intermediates diffuse within and between the photoreceptors and the RPE, and the dependence of phototransduction reactions on the operation of the cycle. These important questions pose exciting challenges for future research on the visual cycle and are certain to continue as the subject of intense interest for Professor Palczewski’s laboratory.
The goal of Professor Palczewski’s laboratory is to:
- Understand the biochemical basis underlying the mechanism of rhodopsin inactivation and restoration of the cGMP level.
- Delineate the biochemical basis underpinning the similarities and differences between rod and cone cell phototransduction.
- Understand the enzymology of the isomerization of all-trans-retinol to 11-cis-retinol in the retina.
- Advance our knowledge about phototransduction in the retina, a system with great experimental advantages, will improve further understanding of similar events in hormonal signaling, cellular communication, and immune regulation, and provide baseline information for further studies of retinal disease processes.
U01 EY025451 (Audacious grant) Palczewski (PI) 05/01/15 – 04/30/20
Title: A two-photon ophthalmoscope for human retinal imaging and functional testing.
Objective: Pursuing a tool to visually monitor vitamin A derivatives in the retina. The team will develop a two-photon microscope capable of measuring the metabolism and distribution of vitamin A derivatives within photoreceptors, at baseline in various retinal diseases and in response to potential therapies.
R01 EY09339 Palczewski (PI) 08/1/92 - 08/31/20
Title: Retinoids in vision
Objective: Flow of retinoids in the eye: chemistry and biochemistry of isomerization processes.
1R01 EY020551 von Lintig (PI) (Palczewski, Co-PI) 04/1/16 - 03/30/20
Title: Carotenoids in Vision
Objective: Understand the function and structure of carotenoid metabolizing enzymes.
1R24EY024864-01 Kern (PI) (Palczewski -collaborator) 04/1/15-03/31/20
Title: Novel therapies to inhibit diabetic retinopathy
Objective: This multi-investigator grant is to complete preclinical studies related to G-coupled protein receptors as drug targets to inhibit diabetic retinopathy.
R01 EY025696 Kefalov (PI) (Palczewski-collaborator) 08/01/16-07/31/20
Title: Pigment dephosphorylation in mammalian rod and cone photoreceptors
Objective: To study the role of visual pigment dephosphorylation in modulating the kinetics of dark adaptation or the susceptibility of photoreceptors to light damage.
Joint Canadian Institute for Advanced Research and Max Planck Society Research Dwayne Miller and Oliver Ernst (PIs). (KP-Member of the Advisory Board) 07/01/14-07/30/20
Title: Molecular Building Blocks of Living Systems (MBB) Program (CIFAR Consortium)
Objective: Facilitate collaboration at the intersection of physics, chemistry, and medicine as related to living cells.
Alcon Research Institute (ARI) grant Palczewski (PI) 08/01/17-07/31/20
Title: Color vision: structure of human cone visual pigments
Objective: Structural biology of cone visual pigments.
R24 027283 Palczewski (PI) 07/01/2017-03/31/2022
Title: Use of systems pharmacology to prevent rod and cone photoreceptor degeneration
Gund-Harrington-CWRU Lu (PI) (Palczewski-collaborator) 7/1/2019-6/30/2020
Title: Nonviral Gene Therapy for Stargardt Disease
UCI SOM Center for Translational Vision Research