Bowes Rickman Laboratory

2351 Erwin Road, AERI Room 5010

Catherine Bowes Rickman, PhD, Principal Investigator

Professor of Ophthalmology

Associate Professor of Cell Biology

Duke Eye Center
2351 Erwin Road, AERI Room 5010
Durham, NC  27710
 
Office: 919-668-0648
Lab: 919-668-0649
Fax: 919-684-3687
Email: bowes007@duke.edu
 
 

Education

B.A.: University of California at Santa Barbara, 1983
 
Ph.D.:University of California at Los Angeles, 1989
 
Postdoctoral Fellow: University of California at Los Angeles, Jules Stein Eye Institute,
 
Previous Appointments
 
Saint Louis University, Assistant Professor, Department of Ophthalmology
 
The University of Iowa Hospitals and Clinics, Associate Faculty, Department of Ophthalmology
 
Duke University, Assistant Professor, Departments of Ophthalmology and Cell Biology
 
 

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.

Support for a role for complement activation 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.

Mouse models of age-related macular degeneration: Currently studies of multiple murine models of AMD are underway.

Human APOE iso

  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 (HFC) diet that develop pathological features similar to the morphologic hallmarks observed in both dry and wet human AMD. The 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 test 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 us to studies that showed therapies targeting Abeta can preserve retinal function in these mice. Validation of these therapeutic targets is currently in clinical trials.
  2. Cfh heterozygous mice: Based on the substantial evidence implicating complement factor H (CFH) in the pathogenesis of AMD we tested the effect of advanced age, exposure to a HFC diet and CFH deficiency (Cfh knock out) or Cfh haploinsufficiency (Cfh hemizygous). Characterization of these mice established a link between the complement system and lipid pathways by demonstrating that (i) CFH and lipoproteins compete for binding in the sub-RPE extracellular matrix such that decreasing CFH leads to lipoprotein accumulation and sub-RPE deposit formation; and (ii) detrimental complement activation within sub-RPE deposits leads to RPE damage and vision loss. This new understanding of the complicated interactions of CFH in development of AMD-like pathology represents a paradigm shift in our understanding of AMD and paves the way for identifying more targeted therapeutic strategies for AMD.
  3. 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. We showed that only the aged His402 expressing mice on HFC diet (CFH-HH~HFC) developed AMD-like pathologies consisting of attenuated rod-mediated visual function, RPE damage and basal laminar deposit formation compared to the Tyr402 expressing mice on HFC diet (CFH-Y~HFC). Analysis of these models establish a causal link between CFH and lipoprotein dysregulation and development of an AMD phenotype. We are the first to establish a functional consequence of the AMD-risk associated His402 form in vivo.