The mechanisms involved in the development of the retinal vasculature are still controversial, but in dog and human we have demonstrated that it occurs by vasculogenesis, the differentiation and coalescence of retinal angioblasts. When the developing retinal vasculature is exposed to hyperoxia, severe vasoconstriction and eventual vaso-obliteratidn occurs in the dog model of oxygen-induced retinopathy (OIR). When this severely compromised vasculature is reintroduced to room air, the retina is hypoxic because of an inadequate blood supply and angiogenesis occurs. To understand this susceptibility to hyperoxia and the angiogenesis that ensues, it is necessary to first understand how the retinal vasculature develops and the cells and signals involved. This proposal will address how the superficial retinal vasculature forms using immunohistochemistry in fetal human retinas. This will also be accomplished by in vitro assessment of the molecules that stimulate retinal angioblast chemotaxis (VEGF, ANG2, SDF-1, and SCF) and presence of their putative receptors on the angioblasts. We have recently demonstrated that dog angioblastSiarei,rnultipotent in that they can become endothelial cells or pericyte-like cells. We wish to better understand the stimuli for their differentiation and fate determination in vitro. We will also evaluate the'ability^angioblasts to build a blood vessel in vitro and their ability to contribute retinal vasculogenesis in vivo. -,;.coic?.;;. Finally, we will employ a novel nonviral gene delivery:system, multilayered magnetic nanoparticles, to control vaso-obliteration and vasoproliferation in thedogsOIR model. Vaso-obliteration will be challenged by using a bioresponse element promoter to turn-on genes that could prevent endothelial cell and angioblast apoptosis in response to hyperoxic insult.-The nanoparticle strategy will also be used to deliver antiangiogenic genes to hyalocytes and proliferating endothelial cells in retinal neovascularization to inhibit angiogenesis. The goal of this proposal is to better understand the development of the retinal vasculature so that we can effectively target both the vaso-obliterative susceptibility and angiogenic response that occurs in OIR and human retinopathy of prematurity. . .;

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009357-16
Application #
7797352
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1992-12-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
16
Fiscal Year
2010
Total Cost
$315,303
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Valapala, Mallika; Edwards, Malia; Hose, Stacey et al. (2015) ?A3/A1-crystallin is a critical mediator of STAT3 signaling in optic nerve astrocytes. Sci Rep 5:8755
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
Park, Tea Soon; Bhutto, Imran; Zimmerlin, Ludovic et al. (2014) Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. Circulation 129:359-72
Edwards, Malia M; Rodríguez, José J; Gutierrez-Lanza, Raquel et al. (2014) Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease. Exp Eye Res 127:252-60
Xin, Xiaoban; Rodrigues, Murilo; Umapathi, Mahaa et al. (2013) Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. Proc Natl Acad Sci U S A 110:E3425-34
Edwards, Malia M; Lefebvre, Olivier (2013) Laminins and retinal vascular development. Cell Adh Migr 7:82-9
Lutty, Gerard A (2013) Effects of diabetes on the eye. Invest Ophthalmol Vis Sci 54:ORSF81-7
Rodrigues, Murilo; Xin, Xiaoban; Jee, Kathleen et al. (2013) VEGF secreted by hypoxic Muller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Diabetes 62:3863-73
McLeod, D Scott; Baba, Takayuki; Bhutto, Imran A et al. (2012) Co-expression of endothelial and neuronal nitric oxide synthases in the developing vasculatures of the human fetal eye. Graefes Arch Clin Exp Ophthalmol 250:839-48

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