Posterior uveitis is a heterogeneous group of potentially blinding inflammatory disorders that primarily involve the retina and/or choroid. While different subtypes of posterior uveitis are known to be autoimmune, infectious and neoplastic, the basic pathogenic mechanisms responsible for these diseases remain unclear. Consistent with recent recognition that different vascular beds throughout the body are characterized by specific sets of cell adhesion molecules and chemoattractants, we hypothesize that the key to understanding the pathogenesis of posterior uveitis, and to developing effective therapeutic interventions, is defining the unique set of molecular signals expressed by retinal microvascular endothelium. Using unique, donor-matched, ocular vascular endothelial cell cultures and cDNA microarray technology, the investigators will study expression of over 8,000 genes by retinal endothelium, under different conditions of stimulation, and in comparison to gene expression by iris and choroidal endothelium. In addition, the investigators will make use of two retinal endothelial cell """"""""probes"""""""", namely, Toxoplasma gondii tachyzoites, infectious forms of a protozoan parasite that preferentially infect the retina, and malignant B cells from patients with primary central nervous system lymphoma, a tumor that also preferentially involves retina. Novel assays will be employed to investigate specificity of binding to, and isolate potential receptors for, these microbes and lymphocytes on retinal vascular endothelium. It is anticipated that these studies will provide new information about the mechanisms that are responsible for homing of leukocytes and microrganisms to the eye in posterior uveitis. This understanding may direct the development of new treatments for posterior uveitis that target specific interactions between the retinal microvascular endothelium and the infiltrating cell or invading microbe. The studies should also have implications for unrelated diseases affecting the retinal circulation, as well as tissue-specific inflammations and infections at other body sites. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014909-03
Application #
6928997
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Shen, Grace L
Project Start
2003-09-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$333,710
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Zamora, D O; Rosenbaum, J T; Smith, J R (2008) Invasion of human retinal vascular endothelial cells by Toxoplasma gondii tachyzoites. Br J Ophthalmol 92:852-5
Choi, Dongseok; Appukuttan, Binoy; Binek, Sierra J et al. (2008) Prediction of Cis-Regulatory Elements Controlling Genes Differentially Expressed by Retinal and Choroidal Vascular Endothelial Cells. J Ocul Biol Dis Infor 1:37-45
Smith, J R; Henderson, W W; Rosenbaum, J T et al. (2008) Cultured human endothelial cells expressing HIV-1 Vpu and Tat support the expansion of malignant B cells from primary central nervous system lymphoma. Br J Ophthalmol 92:297-9
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Smith, Justine R; Choi, Dongseok; Chipps, Timothy J et al. (2007) Unique gene expression profiles of donor-matched human retinal and choroidal vascular endothelial cells. Invest Ophthalmol Vis Sci 48:2676-84
Smith, Justine R; Falkenhagen, Katherine M; Coupland, Sarah E et al. (2007) Malignant B cells from patients with primary central nervous system lymphoma express stromal cell-derived factor-1. Am J Clin Pathol 127:633-41
Coupland, Sarah E; Loddenkemper, Christoph; Smith, Justine R et al. (2005) Expression of immunoglobulin transcription factors in primary intraocular lymphoma and primary central nervous system lymphoma. Invest Ophthalmol Vis Sci 46:3957-64
Falkenhagen, Katherine M; Braziel, Rita M; Fraunfelder, Frederick W et al. (2005) B-Cells in ocular adnexal lymphoproliferative lesions express B-cell attracting chemokine 1 (CXCL13). Am J Ophthalmol 140:335-7

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