Papadakis Integrated Sciences Building (PISB), Room 120, located on the northeast corner of 33rd and Chestnut Streets.
BIOMED Seminar
Title:
Retinal Guanylyl Cyclase: The Enzyme That Enables Vision, Relates to Congenital Blindness, and Presents a Prospective Target for Gene Therapy
Speaker:
Alexander M. Dizhoor, PhD
Hafter Chair Professor in Pharmacology
Pennsylvania College of Optometry (PCO)
Salus at Drexel University
Details:
Some forms of congenital blindness originate from abnormalities in basic signaling mechanisms in photoreceptor neurons of the retina. Photoreceptors respond to light by modulating the permeability of CNG channels located in plasma membrane of their specialized light-sensitive compartment – the outer segment. The open state of the channels is defined by the free concentrations of cyclic guanosine monophosphate (cGMP): the cGMP levels in dark-adapted photoreceptors are sufficiently high to keep the channels open, whereas light reduces cGMP levels, closes CNG channels, and thus hyperpolarizes photoreceptors to initiate the pathway leading to visual perception. Retinal membrane guanylyl cyclase 1 (RetGC1, or GUCY2D) is the main enzyme producing cGMP in rods and cones, a process regulated by Ca2+ sensor proteins, GCAPs, and RD3 protein.
Abnormalities in regulation of RetGC1 by GCAPs and RD3 cause various forms of congenital blindness, ranging from recessive loss of photoreceptor function to dominant degenerative gain-of-function disorders. The processes underlying these forms of blindness can be, at least to a certain extent, replicated and studied in vitro and in vivo in transgenic mouse models created in Pennsylvania College of Optometry. Some of these studies already contributed to a first successful clinical trial of gene therapy for a rare recessive form of GUCY2D-linked blindness, whereas other forms of GUCYD blindness still require conceptualization and development of translational research aiming at the prospective gene therapy. As a part of such efforts, we explore some original paradigms designed for rescuing photoreceptors from degeneration in transgenic models replicating the origins of certain, presently incurable, forms of human retinal dystrophies caused by deregulation of GUCY2D by GCAP or RD3.
Biosketch:
Alexander M. Dizhoor, PhD, is Hafter Chair Professor at Pennsylvania College of Optometry (PCO). Dr. Dizhoor studies molecular mechanisms of retinal function and congenital blindness. He published over 100 papers in this field of study. The research he leads as a PI has been continuously supported by NIH grants from National Eye Institute since 1996, as well as by other extramural funding sources.
Dr. Dizhoor joined PCO (now a part of Salus at Drexel University) in 2002. In recent years, in addition to studying the basic molecular mechanisms of photoreception in the retina, his laboratory became involved in developing prospective approaches to gene therapy of some rare forms of retinal blindness.