Research in Jastrzebska’s lab focuses on understanding the structure and function of the fundamental visual G protein-coupled receptor (GPCR), rhodopsin, under physiological and pathological conditions, and developing pharmacological treatments targeting this receptor. Rhodopsin, abundantly expressed in rod photoreceptors not only transmits the light signal to the brain allowing for object recognition, but it also is associated with degenerative diseases affecting human eyesight. Mutations identified in the rhodopsin gene affect folding, cell surface trafficking, oligomeric organization, and/or function of this receptor, leading to photoreceptor cell death and consequently blindness. We study the molecular basis of this inherited retina pathology called retinitis pigmentosa and focus on discovering novel non-retinoid small molecule modulators to correct the misfolding and mistrafficking of clinically relevant rhodopsin mutants in the context of developing therapeutic strategies preventing vision loss. These pathogenic mutants activate cellular stress response triggering photoreceptors’ death. Thus, the ongoing development of the pharmacological modulators of the apoptotic processes in degenerating retinas presents an alternative therapeutic approach to protect cells of the visual system. In addition, we investigate the role of other GPCR signaling modulation in neuroprotection against acute and chronic retina degeneration and their potential as therapeutic targets. This research aims to make groundbreaking progress in developing small molecule modulators that can effectively target visual GPCRs and prevent disease phenotypes.
To achieve the goals of our projects we use virtual target-based small molecule screenings followed by hit validation in vitro and in vivo using relevant mouse models. We use biochemical, biophysical, molecular biology, and structural approaches, including protein heterologous expression, protein purification from native and expressed cells, tryptophan fluorescence-based functional assays, protein SDS-PAGE electrophoresis, western blotting, DNA cloning, PCR, mutagenesis, agarose gel electrophoresis, bacterial culture, mammalian cell culture, immunostaining, bioluminescence resonance energy transfer, crystallography and mass-spectrometry based techniques.