Davis Heart and Lung Research Institute
473 West 12th Ave, Suite 611B
Columbus, OH 43210
PhD, Shanghai Institute of Plant Physiology, Chinese Academy of Sciences
Post-doctoral Fellow, the Hebrew University of Jerusalem, Israel
Dr. Guo’s earlier work revealed asymmetric and extended interactions between the inhibitory subunit and the two catalytic subunits of PDE6, a key enzyme in phototransduction. He is now studying the sigma-1 receptor, a unique ligand-operated chaperone that does not have any homologs in mammalian genomes. Using genetic models and targeted nanoparticle drug carriers, the Guo lab delineated a specific role of this receptor in protecting retinal ganglion and photoreceptor neurons. While a new sigma-1 receptor function emerges involving chromatin regulations, we visualized via EM predominant sigma-1 distribution in nuclear membranes including the nucleoplasmic reticulum. We are also investigating the molecular mechanism underlying a novel role of the sigma-1 receptor that we identified in autophagosome-lysosome fusion. Dysregulated autophagy has been implicated in retinal degenerative diseases.
The Guo lab research has recently extended to a family of bromo and extraterminal (BET) proteins, dubbed epigenetic readers. BET proteins assemble super-enhancers and transcription factors and translate chromatin marking into activation of RNA polymerase II, thereby turning on the expression of a select set of genes in a cell type and cell state-specific manner. We first observed that inactivating the BET family blocks the phenotypic transition of vascular smooth muscle cells that is the primary cause of restenosis, a lumen narrowing pathology in blood vessels. Most recently, we also found that BET inhibition in degenerate mouse retinas abrogates the resting-to-inflammatory phenotype change of retinal microglia. This microglial cell state transition has been recently found to substantially potentiate retinal photoreceptor degeneration.
Clinical trials targeting either the sigma-1 receptor or the BET family have led to promising outcomes, e.g., in treating cardiovascular disease. Encouraged by these advances, we are collaborating with bioengineers to develop innovative drug delivery strategies to translate our research into effective treatments for large populations, who would otherwise develop blindness or flow-obstructing vascular disease.