The objective of the proposed studies is to test the hypothesis that the process of drusen formation is stimulated by complement-mediated inflammatory events involving retinal pigmented epithelial (RPE) cells. Drusen are extracellular deposits that form between the RPE and Bruch's membrane, and are a significant risk factor for age-related macular degeneration (AMD). In AMD, functional compromise and ultimately death of RPE cells as a consequence of drusen formation is thought to lead to secondary degeneration of retinal photoreceptor cells and visual loss. Studies of age-related human diseases that, like AMD, involve cellular degeneration and the formation of insoluble deposits (e.g., Alzheimer's disease, atherosclerosis and kidney glomerulonephritis) now implicate complement activation and inflammatory events as key elements in disease processes. Data that we generated during the prior application period strongly suggest that complement activation also plays an important role in the formation of ocular drusen. We observed that terminal complement complexes and complement regulatory molecules are present in drusen, as are molecules with potential complement-activating properties. Furthermore, our observations show that RPE cells overlying drusen exhibit a compromised molecular phenotype that is consistent with a well-characterized cellular response to complement attack. Thus, these observations suggest an AMD disease process that is consistent with that of other age-related human diseases. A process that involves a primary pathogenic or age-related stimulus, the effects of which are exacerbated by localized, self-perpetuating, complement-mediated tissue destruction and inflammatory sequelae that persist over decades. The studies proposed here will examine the hypothesis that complement-mediated events contribute both to the process of drusen formation, and to the functional compromise of drusen-associated RPE cells. The studies will target the following specific aims: (1) To determine if RPE cell compromise is the result of complement-mediated attack, (2) To characterize the nature of the complement-mediated processes involved in drusen formation, and (3) To examine RPE cell responses to complement attack utilizing an in vitro model system.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011527-05
Application #
6621752
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1996-08-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$295,000
Indirect Cost
Name
University of California Santa Barbara
Department
Type
Organized Research Units
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Isas, J Mario; Luibl, Volker; Johnson, Lincoln V et al. (2010) Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 51:1304-10
Kochounian, Harold; Johnson, Lincoln V; Fong, Henry K W (2009) Accumulation of extracellular RGR-d in Bruch's membrane and close association with drusen at intercapillary regions. Exp Eye Res 88:1129-36
Radeke, Monte J; Peterson, Katie E; Johnson, Lincoln V et al. (2007) Disease susceptibility of the human macula: differential gene transcription in the retinal pigmented epithelium/choroid. Exp Eye Res 85:366-80
Hageman, Gregory S; Hancox, Lisa S; Taiber, Andrew J et al. (2006) Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 38:592-604
Johnson, P T; Betts, K E; Radeke, M J et al. (2006) Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proc Natl Acad Sci U S A 103:17456-61
Gehrs, Karen M; Anderson, Don H; Johnson, Lincoln V et al. (2006) Age-related macular degeneration--emerging pathogenetic and therapeutic concepts. Ann Med 38:450-71
Hageman, Gregory S; Anderson, Don H; Johnson, Lincoln V et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102:7227-32
Johnson, Patrick T; Brown, Meghan N; Pulliam, Bryce C et al. (2005) Synaptic pathology, altered gene expression, and degeneration in photoreceptors impacted by drusen. Invest Ophthalmol Vis Sci 46:4788-95
Malek, G; Johnson, L V; Mace, B E et al. (2005) Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci U S A 102:11900-5
Anderson, Don H; Talaga, Kevin C; Rivest, Alexander J et al. (2004) Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 78:243-56

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