Seminar: Human CFH Risk Variant Induces AMD Pathology In Mice

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.

Seminar: Retinal Pigment Epithelial Cell Bystander Effects Contribute to AMD Pathology

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.

Seminar: Unraveling The Genetic Risk Spectrum of Age-related Macular Degeneration

Fritsche Flyer

Lars Fritsche from the Department of Biostatistics, School of Public Health, University of Michigan will be delivering a seminar on Unraveling The Genetic Risk Spectrum of Age-related Macular Degeneration on Wednesday, March 11th, 2015 in the Moran Eye Center auditorium.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly Americans. AMD is influenced by numerous factors, including smoking and diet, but the strongest underlying cause is genetic variation. Over the past several years, great strides have been made in our understanding of the genetic disease susceptibility. Common genetic variants in the complement pathway (near the CFH, C3, C2, CFB and CFI genes) and elsewhere (e.g. near ARMS2/HTRA1, TIMP3, LIPC, CETP, VEGFA) have been associated with disease risk. More recently, studies of rarer variants gradually started to identify rare variants with larger risk effects (e.g. in CFH, CFI, or C3).

In this talk I will present an overview and current results of: 1. the ExomeChip study of the International AMD Genomics Consortium, a collaborative effort that jointly genotyped and analyzed > 50,000 AMD cases and controls; and 2. the ongoing AMD Whole Genome Sequencing Study of the Universities of Michigan and Pennsylvania and the National Eye Institute that aims to sequence the genomes of ~6,000 AMD cases and controls. Moreover, I will show examples on how imputation approaches can improve power and increase resolution for the fine-mapping of known AMD susceptibility loci.

Thy-1 Expressed In CNV And Increased In migrating Choroidal ECs In Human Neovascular AMD

Haibo Wang

This abstract was presented today at the 2014 Association for Research in Vision and Opthalmology (ARVO) meetings in Orlando, Florida by Haibo Wang, Yanchao Jiang and M. Elizabeth Hartnett.

Thy-1 regulates VEGF-induced choroidal endothelial cell migration 

Dept of Ophthalmology, John A. Moran Eye Center, The University of Utah-Salt Lake City. 

Purpose: Choroidal endothelial cell (CEC) activation and migration precede the development of choroidal neovascularization in neovascular AMD. Thy-1 is a cell surface protein expressed on different cells, including neurons and endothelial cells. As a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, Thy-1 is located in lipid raft microdomains within the cell membrane, which brings Thy-1 into proximity of signaling molecules including cytoplasmic tyrosine kinases that can modulate adhesive and migratory events. In the retina, Thy-1 is well known as a retinal ganglion cell marker. Given the possibility that Thy-1 might be expressed in CECs, we addressed the hypothesis that upregulated Thy-1 in CECs by age-related stresses contributes to CEC migration.

Methods: Western blots of Thy-1 were determined in retinal pigment epithelial cells (RPE) and CECs. By real time quantitative PCR, Thy-1 mRNA was measured in CECs treated with vascular endothelial growth factor (VEGF) (20 ng/ml), CCL11 (100 ng/ml) or PBS for 24 hours, or in RPE/choroids from young (<40 yrs) and old (>60 yrs) donor eyes. Immunohistochemistry of Thy-1 was performed in posterior globe sections of human retina/RPE/choroids in the maculas of young and old donor eyes with or without AMD.  Colabeling with VE-cadherin was used to identify CECs. CECs transfected with Thy-1 siRNA or control siRNA were stimulated with VEGF, and CEC migration and phosphorylation of VEGF receptor 2 (VEGFR2) were measured. Statistics were performed using ANOVA.

Results:  Thy-1was highly expressed in CECs but not in RPE.  Thy-1 staining was not only detected in the retinal ganglion cell layer, but also in the choroid, and colocalized to a greater extent with VE-cadherin labeled CECs in sections from donors with AMD compared to age-matched controls without AMD.  Thy-1 mRNA was significantly increased in CECs treated with VEGF or CCL11 (p<0.05 vs. PBS) and greater in RPE/choroids from aged donor eyes (p<0.001 vs. young).  Knockdown of Thy-1 in CECs by siRNA transfection significantly inhibited VEGF-induced CEC migration (p<0.001) and VEGFR2 activation.

Conclusions: Thy-1is expressed in CECs and its expression is upregulated by stresses associated with neovascular AMD, including elderly age and increased VEGF.  Upregulated Thy-1 in CECs contributes to VEGF-induced VEGFR2 activation and CEC migration. Future studies into the potential role of Thy-1 in neovascular AMD are being considered. 

Dr. Gregory Hageman Delivers Congressional Briefing

The Moran Eye Center‘s Dr. Gregory Hageman delivered a Congressional Briefing on September 20th along with the Alliance for Eye and Vision Research (AEVR) and partners AMD Alliance International, Alliance for Aging Research, Association for Research in Vision and Ophthalmology (ARVO), European Vision Institute and Lighthouse International.  Dr. Hageman spoke as part of a Congressional briefing as part of International Age-related Macular Degeneration (AMD) Awareness Week 2012.

Dr. Gregory Hageman, Executive Director of the Center for Translational Medicine (CTM) at the John A. Moran Eye Center at the University of Utah related in his address that AMD consists of multiple biological diseases.  Dr. Hageman continued by expressing that a convergence of clinical, biological and genetic data has led to a stronger understanding of the disease and new hope for the development of diagnostics and therapeutic interventions currently underway.

More details of the briefing are available on the NAEVR website here.

Macular pigment imaging in AREDS2 participants: An ancillary study of AREDS2 subjects enrolled at the Moran Eye Center

 

This study by Paul S. Bernstein, Faisal Ahmed, Aihua Liu, Susan Allman, Xiaoming Sheng, Mohsen Sharifzadeh, Igor Ermakov, and Werner Gellermann in IOVS examined the macular pigment in AREDS2 patients.  AREDS2 is a randomized, placebo-controlled study designed to determine whether supplementation with 10 mg of lutein and 2 mg of zeaxanthin per day can slow the rate of progression of age-related macular degeneration (AMD). Continue reading “Macular pigment imaging in AREDS2 participants: An ancillary study of AREDS2 subjects enrolled at the Moran Eye Center”

Seminar: Bärbel Rohrer, Ph.D. “Sublytic Complement Activation in Age-Related Macular Degeneration”

On Tuesday, March 20, 2012 from 4:00 – 5:00pm, Bärbel Rohrer, Ph.D. will be delivering a talk on “Sublytic Compliment Activation in Age-Related Macular Degeneration” at the Eccles Institute of Human Genetics auditorium on the University of Utah campus.

Refreshments will be provided after the seminar for socialization.

Faculty Host: Bryan William Jones, Ph.D.

Questions?  Leave a comment/question here or contact Tracy Marble at 801 581-4820.

Continue reading “Seminar: Bärbel Rohrer, Ph.D. “Sublytic Complement Activation in Age-Related Macular Degeneration””

Notable Paper: Increased Expression of Multifunctional Serine Protease, HTRA1, in Retinal Pigment Epithelium Induces Polypoidal Choroidal Vasculopathy

Efforts to explore chromosome 10q26, a major candidate region associated with age-related macular degeneration (AMD) have proven difficult and controversial.  This particular region of interest is two neighboring genes, ARMS2 and HTRA1.  However, efforts in trying to explore the functional involvement of either HTRA1 or ARMS2 in AMD have proven to be difficult and have often yielded conflicting results.

Continue reading “Notable Paper: Increased Expression of Multifunctional Serine Protease, HTRA1, in Retinal Pigment Epithelium Induces Polypoidal Choroidal Vasculopathy”