Basic Science Research - Duke Eye Center
Basic Science Research


Catherine Bowes Rickman, PhD

The Pathobiology of Age-related Macular Degeneration

We are interested in the molecular mechanisms underlying the development of age-related macular degeneration (AMD). Currently our studies are focused on development and studies of animal models of AMD, AMD pathogenesis and pre-clinical studies of novel therapies for AMD.  
AMD is a late-onset, progressive, neurodegenerative disease with devastating impact on the elderly. This disease occurs primarily in people over the age of 65 years and accounts for approximately 50% of registered blindness in Western Europe and North America. AMD develops as either dry (atrophic) or wet (exudative). AMD is characterized by the accumulation of extracellular lipid- and protein-rich deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and likely contribute to disease pathogenesis and progression similar to intercellular deposits characteristic of other diseases like Alzheimer’s disease, atherosclerosis, and glomerulonephritis. Although the molecular bases of these diseases may be diverse, their pathogenic deposits contain many shared constituents that are attributable, in part, to local inflammation and activation of the complement cascade.

Catherine Bowes Rickman, PhD
Associate Professor of Ophthalmology and Cell Biology
Duke Eye Center
2351 Erwin Road, AERI Room 5010
Durham, NC  27710
phone: (919) 668-0648 office
(919) 668-0649 lab
 Fax: (919) 684-3687
Support for complement in AMD pathogenesis comes from studies implicating variations in the complement factor H (CFH) gene as the strongest genetic factor associated with risk for AMD. The precise mechanisms of complement system dysregulation in AMD are unknown, although there are several candidate molecules. Among these is amyloid beta (Abeta), a constituent of drusen, and known activator of the complement system. Abeta deposits in drusen are associated with activated complement proteins and cell injury. 
Our studies focus on the role of complement activation in the eye, how this contributes to chronic inflammation - a prelude to AMD pathogenesis and progression – and whether Abeta is a trigger of the complement cascade contributing to inflammatory changes, accumulation of protein-rich deposits and RPE damage.
Mouse models of age-related macular degeneration: Currently studies of multiple murine models of AMD are underway including these two:
(1) Human APOE isoform knock-in Mice: We developed a murine model of AMD by combining three of the risk factors for AMD: advanced age, apolipoprotein E isoform expression and exposure to a high-fat, high-cholesterol (HF-C) diet that develop pathological features similar to the morphologic hallmarks observed in both dry and wet human AMD. These disease changes include thick diffuse sub-RPE deposits, lipid- and protein-rich drusen-like deposits, thickening of Bruch’s membrane, patchy regions of RPE atrophy overlying photoreceptor degeneration and, in some animals, spontaneous choroidal neovascularization. This resultant phenotype mimics several of the important phenotypic characteristics of AMD in a temporal, non-fully penetrant and non-invasive manner that is analogous to human AMD progression. We are using this model to study the pathobiology of AMD and to develop therapies. Investigation of this model has revealed that lipid transport dysregulation, inflammation and Abeta deposition contribute to the pathogenesis of the retinal changes observed. This led to identification of novel therapeutic targets for AMD that are we are currently analyzing. In fact, our most recent work shows that therapies targeting Abeta can preserve retinal function in these mice. Validation of these therapeutic targets in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD.
(2) Human CFH transgenic Mice: We developed a model of AMD susceptibility by generating transgenic mice carrying the full length CFH gene encoding the normal (Tyr402) and risk-associated (His402) human forms of factor H. We are using these animals and functional studies of the human factor H protein to determine the functional consequence of the AMD risk-associated change.
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