The retinal pigment epithelial cells (RPE) and the choriocapillaris (CC) have an intimate relationship in the eye. As nearest neighbors, separated only by Bruch's membrane, they rely on each other and assist each other in accomplishing their critical role of sustaining healthy photoreceptor cells. This proposal explores the relationship between these two cell types from the development or birth of choriocapillaris (5-23 weeks gestation) to the dysfunction or death of either cell type in two different forms of age-related macular degeneration (AMD), geographic atrophy (GA) and exudative AMD. The metabolic status and viability of CC will be evaluated using enzyme and immunohistochemistry (IH) and TUNEL labeling. RPE cell viability and function will be investigated with IH and TUNEL labeling. Growth factors (FGF's, VEGF, PIGF, angiopoietins, erythropoietin, stem cell factor, stromal derived factor-1) that the two cells types produce and use for themselves (autocrine) or their neighbor (paracrine), and their cognate receptors will be investigated by IH and bleaching of the tissue. Tube formation in vitro by fetal human endothelial cells in the presence or absence of fetal RPE will be assessed for paracrine and autocrine effects of growth factors using neutralizing antibodies and siRNA. The contribution of leukocytes and complement to CC death and dysfunction and to CNV in AMD will be investigated by IH to identify cell types, leukocyte numbers (nonspecific esterase, CD45, CD68), leukocyte adhesion molecules (ICAM-1, VCAM-1, P-selectin), and pro-inflammatory (TNFa, IL6, IL8, MCP-1) and angiogenic (FGF's, VEGF, PIGF, angiopoietins) cytokines. The spatial relationship between complement factor H, attack complex, leukocytes and CC viability will also be investigated. Using our alkaline phosphatase flat-embedding technique in which CC vascular density and percent of Bruch's membrane covered with RPE can be quantified, we have established and will continue to investigate the mutualistic symbiotic relationship between CC and RPE. This analysis will permit us to establish how this relationship is disrupted in GA and exudative AMD. The goal of this proposal is to better understand the relationship between these two neighboring cell types and elucidate important factors that could be targeted to maintain or improve this healthy relationship.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016151-05
Application #
7860537
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2006-09-01
Project End
2012-04-30
Budget Start
2010-07-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$354,716
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lutty, Gerard A (2017) Diabetic choroidopathy. Vision Res 139:161-167
Edwards, Malia M; McLeod, D Scott; Bhutto, Imran A et al. (2017) Subretinal Glial Membranes in Eyes With Geographic Atrophy. Invest Ophthalmol Vis Sci 58:1352-1367
Nakanishi, Masataka; Grebe, Rhonda; Bhutto, Imran A et al. (2016) Albumen Transport to Bruch's Membrane and RPE by Choriocapillaris Caveolae. Invest Ophthalmol Vis Sci 57:2213-24
McLeod, D Scott; Bhutto, Imran; Edwards, Malia M et al. (2016) Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 57:5843-5855
Bhutto, Imran A; McLeod, D Scott; Jing, Tian et al. (2016) Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br J Ophthalmol 100:720-6
Edwards, Malia M; McLeod, D Scott; Bhutto, Imran A et al. (2016) Idiopathic preretinal glia in aging and age-related macular degeneration. Exp Eye Res 150:44-61
Sinha, Debasish; Valapala, Mallika; Shang, Peng et al. (2016) Lysosomes: Regulators of autophagy in the retinal pigmented epithelium. Exp Eye Res 144:46-53
Lutty, Gerard A (2015) Adult Human Choroid: An Alymphatic Tissue? Invest Ophthalmol Vis Sci 56:7417
Kambhampati, Siva P; Clunies-Ross, Alexander J M; Bhutto, Imran et al. (2015) Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina. Invest Ophthalmol Vis Sci 56:4413-24
Schroedl, Falk; Kaser-Eichberger, Alexandra; Schlereth, Simona L et al. (2014) Consensus statement on the immunohistochemical detection of ocular lymphatic vessels. Invest Ophthalmol Vis Sci 55:6440-2

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