Rui Chen, Professor, Baylor College of Medicine will be delivering a seminar on “Genetics, Mechanism, And New Model Systems For Human Inherited Retinal Diseases” on Wednesday February 27th, 2019 at 12:00pm in the Moran Eye Center auditorium. He will also deliver a Grand Rounds Presentation at 8:00am, also in the the Moran Eye Center auditorium.
Abstract: In the last decade, our group has been focusing on understanding the genetics and molecular mechanism of human inherited retinal diseases (IRD). Currently, about 40% of cases remain unexplained by coding mutations in known IRD genes, representing one of the most significant gaps in our current knowledge of the disease. I will be presenting our current efforts to identify novel IRD disease genes and mutations and follow up functional studies through a combination of next generation sequencing, in vitro and in vivo functional assay, and single cell genomics approaches. In addition, our recent results of developing new systems to model IRD, including organoid and non-human primate, will be discussed.
John Flannery, Professor, University of California, Berkeley will be delivering a seminar on “Engineering Gene Therapies for Retinal Degenerations” on Wednesday February 20th, 2019 at 12:00pm in the Moran Eye Center auditorium. He will also deliver a Grand Rounds Presentation at 8:00am, also in the the Moran Eye Center auditorium.
Abstract: Inherited retinal diseases (IRDs) lead to the progressive loss of rods and cones, beginning in the peripheral retina and underlie blindness in children and adults into middle age. IRDs can result from defects in >50 genes making gene replacement therapies costly or ineffective. An alternative approach is to endow light sensitivity to downstream neurons of the inner retina that survive following photoreceptor loss, by genetic introduction of a light-sensitive signaling protein. A number of light-sensitive signaling proteins have been tested, including the ion channel channelrhodopsin and ion pump halorhodopsin, chemically engineered mammalian receptors and two G- protein coupled receptor (GPCR) opsins that are native to the retina, rhodopsin of rod photoreceptor cells and melanopsin of intrinsically photosensitive retinal ganglion cells. These light-gated systems, when delivered to the surviving neurons of the blind retina using adeno-associated viruses (AAVs), restore light sensitivity, transmission of light-driven activity to higher order visual centers in the brain, and both innate and learned visually guided behaviors. However, each of these approaches encounters a significant limitation. The microbial opsins and the chemically engineered receptors have fast kinetics and follow high frequency modulation of light (~20 Hz) but have a low sensitivity to light (requiring intensities of very bright outdoor light). In contrast, ectopic expression of rhodopsin and melanopsin are extremely sensitive to light (responding to indoor light), but so slow (seconds) that they may not support patterned vision and movement of the subject and of visual objects. Moreover, the systems tested to date operate over a relatively narrow range of intensities. In contrast, normal photoreception combines speed with high sensitivity and adaptation that permits a sharp intensity-response curve to shift over 9 orders of magnitude. The sensitivity and adaptation emerge from the properties of G-protein signaling pathway of photoreceptor cells that both amplifies and modulates the light response. Our goal was to overcome the shortcomings of current vision restoration approaches by searching for a GPCR that could provide fast, sensitive and adapting light responses to surviving cells of the blind retina. Cone opsins are G-protein coupled receptors of cone outer segments in the vertebrate retina. Like the rhodopsin of rods, cone opsins are highly sensitive and adapt to light over many orders of magnitude. We find that, when virally delivered to retinal ganglion cells, medium wavelength cone opsin (MW-opsin) is as sensitive to light as rhodopsin under physiological stimulation parameters, but displays 10-fold faster kinetics. MW-opsin restores discrimination between flashing and constant light and between line patterns of different orientation, in both static and moving displays on a standard LCD computer screen.
Maureen Neitz, Ray H. Hill Chair in Ophthalmology; University of Washington will be delivering a seminar on “Myopia: a major world-wide problem that can be solved” on Wednesday January 16th, 2019 at 12:00pm in the Moran Eye Center auditorium. She will also deliver a Grand Rounds Presentation at 8:00am, also in the the Moran Eye Center auditorium.
Abstract: Nearsightedness (myopia) is an emergent global health problem of staggering proportion, which has driven the hunt for genetic risk factors, with the ultimate goal of gaining insight into the underlying mechanism, and providing new avenues of intervention. The fundamental defect—a slightly elongated eyeball—causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness from a too-long-eyeball remain. These include increased risk of cataracts, glaucoma, retinal detachment and retinal degeneration. Recently, haplotypes of the long and middle wavelength cone photopigment genes that cause a strong splicing defect have been associated with high myopia. In the clinical talk, I will discuss our work to develop and test eyeglasses designed to reduce contrast on the retina as a means of slowing eye growth in myopic children. In the basic science talk I will discuss work to investigate the association between haplotypes of the long wavelength photopigment gene and juvenile onset myopia. In total, the work I will present provides new insight into the cause and prevention of myopia.
Zhuo-Hua Pan, Edward T. and Ellen K. Dryer Endowed Professor; Professor of Dept. of Ophth., Vis. Anatomical Sciences; Scientific Director, Ligon Research Center of Vision, Kresge Eye Institute; Wayne State University School of Medicine; Wayne State University School of Medicine will be delivering a seminar on “Optogenetic Approaches for Vision Restoration” on Wednesday October 10th at 12:00pm in the Moran Eye Center auditorium. He will also deliver a Grand Rounds Presentation at 8:00am, also in the the Moran Eye Center auditorium.
Abstract: Severe loss of photoreceptor cells in inherited or acquired retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, can result in partial or complete blindness. My laboratory has been exploring and developing optogenetic approaches to treating blindness by expressing genetically encoded light sensors, such as channelrhodopsin- 2 (ChR2), in surviving inner retinal neurons to impart light sensitivity to retinas that lack photoreceptor cells. Proof-of-concept studies have demonstrated the feasibility of restoring retinal light responses and visually guided behaviors in animal models. Optogenetic therapy using ChR2 for vision restoration is currently in clinical trial. Our ongoing efforts focus on the development of better ChR variants and effective treatment strategies. In particular, we recently employed a transgenic blind mouse model combining with animal behavioral assays, which enables us to quantitatively assess the efficacy of different optogenetic tools and retinal targeting strategies, as well as to investigate the impact of retinal remodeling on optogenetic vision restoration.
Catherine Bowes Rickman, Professor of Ophthalmology and of Cell Biology at Duke Eye Center, Duke University School of Medicine will be delivering a seminar on “Human CFH Risk Variant Induces AMD Pathology In Mice” on Wednesday, May 23rd at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Age-related macular degeneration (AMD) is the most common cause of blindness among elderly people in the developed world. There is a growing body of evidence based on biochemical, genetic and cell biology that implicates the alternative pathway of complement in the development of AMD. In particular, the complement factor H (CFH) gene, where a nucleotide change results in a tyrosine (Y) to histidine (H) exchange in short consensus repeat 7 (amino acid 402), increases the AMD risk dramatically. CFH is the soluble regulator of the alternative pathway of complement, and is essential in slowing the spontaneous proteolysis or “tickover” of C3→C3b in the plasma. Although it is now apparent that dysregulation of the complement cascade, and of the alternative pathway in particular, is an important predisposing step in AMD development – how to best target complement dysregulation pharmacologically remains undefined. A critical unmet need is to provide evidence supporting the use of therapies targeting complement inhibition for dry AMD in relevant AMD models. We have developed AMD mouse models that faithfully recapitulate many aspects of AMD that – like AMD – are based on multiple risk factors including advanced age, immune system dysregulation and consumption of a high-fat, cholesterol-enriched Western- style diet. These chronic early/intermediate AMD models provide the first opportunity to test the efficacy of targeted immune-based therapies. These models will also likely help to unravel why therapies targeting complement proteins have had limited success in treating humans with AMD to date. I will be describing these models and the outcomes of preclinical testing of therapies targeting the complement system.
Barbel Rohrer, the SmartState Endowed Chair in Gene and Pharmacological Treatment Of Retinal Degenerative Diseases at Medical University South Carolina will be delivering a seminar on “Retinal Pigment Epithelial Cell Bystander Effects Contribute to AMD pathology” on Wednesday, April 18th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Retinal pigment epithelium damage in age-related macular degeneration is triggered in many different locations, suggesting that damage occurs in susceptible areas, while delaying damage in more resilient areas. I will be describing experiments to distinguish two different mechanisms that would mediate the bystander effect: transfer of a signal to the recipient cells by exosomes; or the spread of information by means of communication via gap junctions.
Maureen A. McCall, Professor and Kentucky Lions Eye Research Endowed Chair, at University of Louisville will be delivering a seminar on “Diverse Glycinergic Receptor Subunits & Retinal Ganglion Cell Visual Function” on Wednesday, March 21st at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: In the retina excitatory signaling lays down the basic foundation of visual processing and inhibition shapes excitation to produce the diverse visual responses of its almost 40 different ganglion cell types. Much of inhibition occurs from the inputs of the ~50 amacrine cells (ACs). Approximately half of these amacrine cells are GABAergic and the others are glycinergic. This is unlike the rest of the CNS, where either GABA or glycine is the primary inhibitory neurotransmitter and there are fewer interneurons. AC inputs mediate feedforward, feedback, crossover and serial inhibition that ultimately shape the excitatory output of bipolar cells (BCs), as well as the responses of GCs. In general, GABA inhibition refines spatial responses (object size, shape and location in space and direction of object motion and glycine inhibition shapes temporal responses (object motion and velocity, and the timing of responses to standing contrast. This is a simplistic view, belied by recent studies suggesting that each AC type may uniquely shape visual function and by extension must be crucial to mechanisms that control the diversity of visual responses of the ~40 GC types that form parallel processing channels and establish the framework for all subsequent vision. We know from BCs that inhibitory diversity is enhanced by expression of different inhibitory subunits with different deactivation kinetics, e.g., GABAA, GABAC and. A role for GlyRα subunit diversity is clear in both spinal cord and brainstem, where individual.
GlyRαs create a variety of synaptic interactions to tune the postsynaptic response and modulate different functions15-17. Because the retina has a wider diversity of interneurons (ACs), and it is the only structure that expresses all 4 GlyRα subunits, in addition to GABARs, we hypothesize that this variety contributes substantially to GC visual function. I will discuss the distribution and function of glycinergic receptor isoforms across the retina and retinal ganglion cells. I will describe what we have found about the roles of glycine subunit specific inhibition in shaping the visual responses of retinal ganglion cells.
Lois E. H. Smith, Professor of Ophthalmology at Harvard Medical School, Boston Children’s Hospital will be delivering a seminar on “Photoreceptor Energy Metabolism Directs Neovascular Retinal Disease” on Wednesday, March 14th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Neuronal energy demands are met by a tightly coupled and adaptive vascular network that supplies nutrients and oxygen. The retina is one of the highest energy-consuming organs, exceeding the metabolic rate of the brain; blood vessels grow and regress in reaction to changes in these high demands. Reduced nutrients and reduced oxygen availability instigate compensatory albeit misguided pathological neovascularization in proliferative retinopathies. Conversely, impaired retinal ganglion cell and photoreceptor survival are correlated with abrogated vascular development and as neurons degenerate, the retinal vasculature atrophies to match the reduced metabolic requirements. In mice, photoreceptor degeneration is associated with thinning of the choroid and inner retinal blood vessels. Conditions such as diabetic retinopathy, vaso-proliferative retinopathy of prematurity and neovascular age-related macular degeneration (AMD) have been characterized as diseases of the vasculature. However, it is becoming more evident that the metabolic needs of the neural retina profoundly influence blood vessel supply in development and in disease.
Retinal oxygen sources and the vaso-proliferative response to low oxygen levels have been well characterized. However, understanding the specific fuels used in the retina to generate ATP and supply building blocks for biosynthesis, as well as understanding the vaso-proliferative response to the lack of fuel are also key to neurovascular development. The metabolic and energy needs of the retina have been assumed to be met by glucose, as the retina is part of the CNS, and the brain relies almost exclusively on glucose. There are two primary pathways that cells can use to generate ATP from glucose, glycolysis and oxidative phosphorylation. However, Cohen and Noell concluded in 1960 that a substantial portion of the energy produced through oxidation by the retina (around 65%) was not derived from glucose. We recently showed that the retina (photoreceptors) can also oxidize lipid through fatty acid β-oxidation to produce ATP, accounting for the energy gap noted by Cohen. Both glucose and lipid metabolism are forces that shape the vascular supply of the eye in development and in vaso-proliferative eye diseases.
Xi-Qin Deng, Associate Professor of Cell Biology, and the Joanne I Moore Professor of Pharmacology at University of Oklahoma Health Sciences Center will be delivering a seminar on “cGMP/PKG signaling regulation of endoplasmic reticulum homeostasis in CNG channel deficiency” on Wednesday, January 24th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Mutations in the CNGA3 and CNGB3 genes that encode the cone cyclic nucleotide-gated (CNG) channel subunits account for about 80% of all cases of achromatopsia and are associated with progressive cone dystrophies. Cone photoreceptors degenerate over time in patients and in mouse models of CNG channel deficiency. Over the last several years, my laboratory has been investigating the cellular mechanisms of cone degeneration using mouse models with CNG channel deficiency. Upon binding of cyclic guanosine monophosphate (cGMP) under dark conditions, CNG channels open and permit the influx of the calcium and sodium ions necessary to maintain the dark current and cellular calcium homeostasis. We have found CNG channel deficient-cones undergo endoplasmic reticulum (ER) stress-associated apoptosis. All three arms of ER stress are activated in CNG channel deficiency. We also showed elevated cGMP/ cGMP-dependent protein kinase (PKG) signaling in CNG channel deficiency and cone protection following cGMP depletion or PKG inhibition. Moreover, we obtained evidence connecting ER calcium channel dysregulation with ER stress and cone death. The current effort aims to determine the cGMP/PKG signaling regulation of ER homeostasis in CNG channel-deficient cones.
Wei Li, Chief and Senior Investigator at the National Eye Institute/National Institutes of Health, Retinal Neurophysiology Section will be delivering a seminar on “Living In The Cold – Hibernation And Retinal Neurobiology” on Wednesday, December 18th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: We are interested in understanding how the retina adapts to extreme metabolic conditions, such as those experienced by hibernating animals. We believe that metabolism is one of the core issues pertaining to the health and pathological change in the retina. By studying hibernating animals (the ground squirrel), we hope to identify strategies that can help the retina better cope with metabolic stresses that feature in retinal disease. In this presentation, I will discuss several adaptive features of the ground squirrel retina during hibernation.
Samer Hattar, Chief and Senior Investigator at the National Institutes of Mental Health/National Institutes of Health will be delivering a seminar on “Retinal and Brain Circuits Underlying the Effects of Light on Behavior” on Wednesday, September 6th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: In this presentation, I will talk about how environmental light through photoreceptors in the retina reaches the brain to influence our internal ,timing, sleep, mood and learning. I will provide detailed retinal circuits, and new brain regions that are responsible for the effects of light on each aforementioned function. In the process, my presentation would be applicable to our modern lifestyle where we extended the day into the night by using artificial lighting and electronic devices that are delaying our sleep onset and leading to sleep disruption and debt. These changes could have major societal impacts that I am going to discuss.
Christine Curcio, Professor of Ophthalmology at University of Alabama At Birmingham School of Medicine will be delivering a seminar on “The 411 on subretinoid deposits in age-related degeneration” on Wednesday, June 8th at 12:00 Noon in the Moran Eye Center auditorium.
Vladimir Kefalov, Professor of Ophthalmology and Visual Sciences at Washington University in St. Louis will be delivering a seminar on “Calcium Homeostasis in Mammalian Rod and Cone Photoreceptors” on Wednesday, May 11th at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Calcium plays an important role in the function and health of photoreceptors. Calcium modulates the phototransduction cascade and controls the response sensitivity, response kinetics, and adaptation. Abnormal calcium homeostasis, associated with mutations in multiple phototransduction proteins, has also been suggested to cause retinal degeneration and blindness. This talk will present the results of our recent studies on the mechanisms for extruding calcium from mammalian photoreceptors. We have identified novel mechanisms for regulating calcium in both rods and cones. The implications of our findings for the function and survival of mammalian photoreceptors will also be addressed
David Copenhagen, Professor of Ophthalmology and Physiology at University of California, San Francisco will be delivering a seminar on “Photoreception In Fetal And Newborn Mice: Actions On Behavior And Vascular Patterning In The Eye” on Wednesday, April 6th at 12:00 Noon in the Moran Eye Center auditorium.
Melanopsin-mediated photoreception in fetuses and young neonatal mice.
The newly discovered melanopsin-expressing photoreceptors in the eye are born around mid fetal gestation and well before rod and cone-mediated visual signaling emerges (~postnatal day 10) in mice. Our research focuses on understanding what visual functions are facilitated by photo activated melanopsin cells in fetal and neonatal animals. I will discuss also our studies directed toward elucidating signaling pathways activated by melanopsin cells in the eye.