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 complement in AMD pathogenesis comes from studies implicating variations in the complement factor H (CFH) gene as a strong 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: The AMD mouse models we have developed provide an in vivo means to interrogate the pathogenic contribution of genetic, inflammatory and environmental factors to AMD onset and progression. Our murine models of AMD include:
(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. 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.
(3) 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 high-fat, high-cholesterol (HFC) diet and complement factor H deficiency (Cfh knock out) or Cfh haploinsufficiency (Cfh heterozygous). 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.
Education and Training
- University of California - Los Angeles, B.A. 1983
- University of California - Los Angeles, Ph.D. 1989
- Duke University School of Medicine, Associate Professor with Tenure, Ophthalmology And Cell Biology
- University of California - Los Angeles, Postdoctoral Fellow, Jules Stein Eye Institute
- Saint Louis University, Assistant Professor, Ophthalmology
- University of Iowa, Associate Faculty, Ophthalmology
- Duke University School of Medicine, Assistant Professor, Ophthalmology And Cell Biology
- Duke University School of Medicine, Associate Professor, Ophthalmology And Cell Biology
Selected Grants and Awards
- Complement factor H modulates lipoprotein clearance in AMD
- Genetic and Genomics Training Grant
- Cellular and Molecular Dynamics of Retinal Microglial in the Context of Photoreceptor Degeneration
- Training Program in Developmental and Stem Cell Biology
- RPE Trophic Activity for Retinal Protection
- HDL - a therapeutic target for age related macular degeneration.
- Prevention of Early/Intermediate AMD using Anti-C5 Immunotherapy
- Dose range finding study for AAV8.CBA.humanFH vectors in CFH-deficient Mice
- Genetics Training Grant
- Testing the effect of a CFH agonistic monoclonal PEG-Fab
- Innate immunity, lipoproteins and AMD progression
- Gemini Therapeutics, Inc.- SRA
- The Role of Exosomes in Dry AMD
- Regulation of Sub-RPE Deposit Formation in AMD by Local and Systemic Complement Factor H
- Immunohistochemistry (IHC) of Photothermal and Photomechanical Laser Lesions in the Retina to Support the BSELL Project
- Targeting Amyloid beta for the treatment of dry Age-related Macular Degeneration
- Ocular Pharmacology and Therapeutics Conference
- Complement and Pathogenic Mechanisms of AMD
- A non-canonical role for b-secretase in AMD
- Candidate Genes for Primary Open Angle Glaucoma
- The Molecular Basis of Pseudoexfoliation Syndrome
- Proteome Map of the Photoreceptor Cell
- Murine AMD Model Based on Constellation of Known Human AMD Risk Factors
- Characterization of Genes in Normal and AMD Retinas
- Characterization of Genes in Normal and AMD Retinas