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: 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.