Age-related macular degeneration (AMD) is characterized by the progressive loss of vision in the central visual field attributable to atrophic, exudative and/or hemorrhagic changes in the macula. One of the hallmarks of AMD is the accumulation of extracellular deposits known as drusen between the retinal pigmented epithelium (RPE) and its blood supply, the choriocapillaris. In this project, our working hypothesis is that specific drusen-associated molecules accumulate in the cytoplasm, or along the basal surface, of """"""""compromised"""""""" RPE cells in advance of actual drusen formation.
One aim of the proposed research, therefore, is to characterize the role of the RPE in drusen biogenesis. Secondly, having confirmed that a number of drusen-associated molecules do, in fact, have local cellular sources in the retina, RPE, and/or choroid, we propose to determine whether any of these local cell types make a significant biosynthetic contribution to drusen. Accordingly, we propose to identify the relevant cell types, and to determine whether any of these drusen-associated molecules are expressed differentially in individuals with drusen or AMD. Differential expression of gene transcripts in target tissues [cells] in the retina, RPE, and choroid will be analyzed quantitatively using an automated fluorogenic detection system based upon the reverse transcriptase-polymerase chain reaction (RT-PCR). In pursuing these studies, we hope to determine whether changes in the expression of one or more of these genes contributes in a significant way to the cascade of degenerative changes that ultimately manifests itself as AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011521-06
Application #
6518559
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1996-08-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
6
Fiscal Year
2002
Total Cost
$328,500
Indirect Cost
Name
University of California Santa Barbara
Department
Type
Organized Research Units
DUNS #
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
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
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
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
Johnson, Patrick T; Lewis, Geoffrey P; Talaga, Kevin C et al. (2003) Drusen-associated degeneration in the retina. Invest Ophthalmol Vis Sci 44:4481-8
Johnson, Lincoln V; Leitner, William P; Rivest, Alexander J et al. (2002) The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A 99:11830-5
Leu, Sergiu T; Batni, Suchitra; Radeke, Monte J et al. (2002) Drusen are Cold Spots for Proteolysis: Expression of Matrix Metalloproteinases and Their Tissue Inhibitor Proteins in Age-related Macular Degeneration. Exp Eye Res 74:141-54
Anderson, Don H; Mullins, Robert F; Hageman, Gregory S et al. (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134:411-31

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