TRPV4 Regulates Calcium Homeostasis, Cytoskeletal Remodeling, Conventional Outflow and Intraocular Pressure

Krizaj glaucoma

Glaucoma is the main cause of irreversible blindness in the world. In most common types of the disease, the optic nerve is damaged by an increase in intraocular pressure (IOP) which blocks fluid drainage through canals in the eye. There is currently no cure, however, the disease can be treated by lowering IOP. Unfortunately, all IOP-lowering drugs that in the market today target the secondary drainage pathway which mediates only 5-15% of fluid outflow. Therefore, the main goal in glaucoma research has been to identify targets in the primary outflow pathway mediated through the trabecular meshwork tissue. David Krizaj’s group at the Moran Eye Institute (University of Utah School of Medicine) has done just that.

In a paper just published in Scientific Reports, they identify TRPV4, a mechanosensitive ion channel, as the main trabecular target of increased IOP. This highly collaborative project combined genetic, molecular, whole animal approaches with bioengineered nanoscaffold models of glaucoma and drug discovery to show that activation of the channel mimics the trabecular changes in glaucoma whereas elimination of the TRPV4 gene or systemic exposure to TRPV4 inhibitors protected mice from the disease. In collaboration with Glenn Prestwich’s group in Medicinal Chemistry at the University of Utah, the team synthesized new eye drops which lowered IOP to levels seen in control mice. By targeting the primary outflow pathway, this study promises to bring new, effective cures that complement current glaucoma treatment. The primary authors of the study are Dr. Dan Ryskamp, Amber Frye and Dr. Tam Phuong.

Seminar: Linking Metabolism, Vascular Maintenance, and Photoreceptor Homeostasis in the Retina

Peter W

Peter Westenskow, Research Associate, Department of Cell and Molecular Biology, The Scripps Research Institute Staff Scientist, Lowy Medical Research Institute will be delivering a seminar on Linking Metabolism, Vascular Maintenance, and Photoreceptor Homeostasis in the Retina on Wednesday, July 2nd 15th at Noon  in the the Moran Eye Center auditorium.

Abstract: Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. The architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. In my talk I will discuss the importance of retinal neurovascular units in the retina, focusing specifically on work demonstrating that photoreceptors can generate a bioreactive lipid that activates angiogenesis in the choriocapillaris. I hope to provide novel perspectives on the physiology of complex neurovascular units and discuss how these studies may inform future neurotrophic strategies for treating some of the most severe neurodegenerative diseases.

Seminar: Fat3 – An Unusual Cadherin Regulating Retinal Lamination and Stratification

Michael D Flyer

Michael Deans, Assistant Professor and Director of Research, Otolaryngology, University of Utah will be delivering a seminar on Fat3 – An Unusual Cadherin Regulating Retinal Lamination and Stratification on Thursday, July 2nd 24th at Noon  in the the Moran Eye Center auditorium.

Abstract: Neurons receive signals through dendrites that vary widely in number and organization, ranging from one primary dendrite to multiple complex dendritic trees. For example, retinal amacrine cells project primary dendrites into discrete strata of the inner plexiform layer and only rarely extend processes into other retinal layers. We have shown that the atypical cadherin Fat3 ensures that ACs develop this unipolar morphology. AC precursors are initially multipolar, but lose neurites as they migrate through the neuroblastic layer. In fat3 mutants, pruning is unreliable and ACs elaborate two dendritic trees: one within the IPL and a second projecting away from the IPL that stratifies to form an additional synaptic layer. More recently we have found that Fat3 is regulated by RNA processing and that one alternatively spliced isoform binds to the Kinesin subunit Kif5b. One exciting hypothesis that we are currently testing is that Kinesin trafficking regulates Fat3 subcellular distribution, thereby mediating Fat3-dependent dendrite formation.

Seminar: Cellular and Molecular Mechanisms of Optic Cup Morphogenesis

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Kristen Kwan, Assistant Professor of Human Genetics, University of Utah will be delivering a seminar on Cellular and Molecular Mechanisms of Optic Cup Morphogenesis on Wednesday, June 24th at Noon  in the the Moran Eye Center auditorium.

Abstract: Developmental defects in eye structure can cause visual impairment in newborns.  These defects often arise very early in eye development, when the basic structure of the eye is generated during optic cup morphogenesis, which transforms the nascent optic vesicle, via a series of complex cell and tissue rearrangements, into the optic cup.  Using zebrafish as our model system and a combination of 4-dimensional live imaging, computational methods, and molecular genetics, we are directly visualizing optic cup morphogenesis and determining underlying mechanisms.  This talk will be focused on our recent work aimed at understanding choroid fissure formation and its disruptions in a particular zebrafish model of ocular coloboma, as well as the role of extracellular matrix proteins and adhesion in driving optic cup formation.

Müller Cell Metabolic Chaos During Degeneration

Muller-cell-chaos1 copy

This abstract was presented today at the 2015 Association for Research in Vision and Opthalmology (ARVO) meetings in Denver, Colorado by  Rebecca L. PfeifferBryan W. Jones and Robert E. Marc.

Purpose: Müller cells (MCs) play a critical role in glutamate (E) metabolism and carbon skeleton cycling in retina. MCs demonstrate changes in metabolism and morphology during retinal degeneration. The timing, extent, regulation, and impacts of these changes are not yet known. We evaluated metabolic phenotypes of MCs and evaluated their capacity to transport glutamate during degeneration.

Methods: Retinas were harvested from wild-type (WT) and rhodopsin Tg P347L rabbits, divided into chips mounted on filters, and incubated in Ames medium with 5 mM D-aspartate (D-Asp), D-glutamate (D-Glu), or D-glutamine (D-Gln) for 10 min at 35 deg to explore transport and metabolism. Chips were fixed in mixed aldehydes and resin embedded for computational molecular phenotyping (CMP) of a range of L- and D-amino acid markers and selected proteins including glutamine synthetase (GS) (J Comp Neurol. 464:1, 2003).

Results: CMP revealed wide variations in metabolite levels across individual MCs from Tg P347L retinas, generating chaotic patterns. GS decreased significantly while glutamine levels (Q) increased, although to varying degrees. Remarkably, E levels were variable and much higher in some MCs than normal, but did not correlate (inversely) with GS levels. Transport experiments using D-Glu, D-Asp, and D-Gln showed that alterations in MC metabolites are not the product of defective transporters, in contrast to previous reports. These results are also inconsistent with conventional models of GS-based E-Q metabolism and microenvironmental regulation of MC phenotypes.

Conclusions: These observations suggest three conclusions. (1) Although degeneration of the retina is certainly the trigger, MC phenotype changes are not a coherent response to the surrounding microenvironment but are, rather, uncoordinated individual MC responses. (2) Although GS is accepted as the primary enzyme responsible for the conversion of E to Q in the normal retina, alternative pathways appear unmasked in the degenerate state. (3) It has been previously hypothesized that MCs in retinal degenerations exhibit deficient E transport. Our experiments show no transport deficiency. This indicates that chaotic metabolite levels emerge from changes in individual MC metabolic processing.

Seminar: How Inhibiting The Dimerization Of Vitamin A and/or Catalyzing The Reduction of Quinones May Prevent Retinal Degeneration

Ilyas W Flyer

Ilyas Washington from Columbia University Medical Center will be delivering a seminar on How Inhibiting The Dimerization Of Vitamin A and/or Catalyzing The Reduction of Quinones May Prevent Retinal Degeneration on Wednesday, February 11th, 2015 in the Moran Eye Center auditorium.

Abstract:  Many human conditions, originating from multiple genetic and environmental pressures, converge to overproduce superoxide radical anions. The bulk synthesis of cellular superoxides is believed to result from redox cycling of the quinone, coenzyme q. We have designed small molecules to control quinone redox cycling and correct superoxide fluxes as a means to prevent retinal degeneration.

Moran Eye Center Sets Up Eye Camp In Guatemala

The Moran Eye Center travels globally as one of their missions for International Outreach and provides eye care in remote places around the world that are medically underserved from an ophthalmology perspective.

This is a short video showing the Moran Eye Center setting up an eyecamp in Salma, Guatemala on Dec. 9th. This includes moving furniture at the detination, cleaning, and setting up surgical equipment, operating tables, microscopes, and other allied equipment. This effort involves months of planning and ultimately the goal is to improve or restore vision in over 250 patients who travel from all over Guatemala to receive free care.

Call For Proposals, Vision Art Exhibit

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The Moran Eye Center is issuing a call for proposals for two different art exhibits related to vision that we are curating: a permanent collection which will be housed in the new Mid-Valley Health Center and an exhibit that will be held at Art Access Gallery from April 17 – May 8th, 2015.

The deadline for the Mid-Valley Moran Eye Center location is Nov. 28th.

The deadline for the Art Access show is January 30th.

Please review the pdf linked here for more information and let us know here in the comments or by email at webvision@hsc.utah.edu if you have any questions.

 

Image Credit: Bryan William Jones, Ph.D.

Seminar: Circadian Dysfunction In The Pathogenesis Of Diabetic Retinopathy

Seminar Maria Grant

Maria Grant, Professor and Marilyn K. Glick Senior Chair, from the Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology and Department of Cellular and Integrative Physiology, Indiana University School of Medicine will be delivering a seminar in the Moran Eye Center auditorium on “A Broken Clock: Circadian Dysfunction In The Pathogenesis Of Diabetic Retinopathy” on Wednesday, October 1st at 11:00am.

Abstract:

Many disorders are characterized by circadian rhythm abnormalities, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian “clock genes” commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors. However, circadian clock dysfunction impacts diabetic complications including diabetic retinopathy. In this presentation, the impact of mutations in clock genes on retinal vascular function will be discussed. Circadian dysregulation of stem cells release from the bone marrow in diabetes will be described.