During pathological neovascularization of the retina, normally quiescent vascular endothelial cells proliferate and migrate through the extracellular matrix (ECM), resulting in the formation of new blood vessels. If these newly formed vessels leak fluid, hemorrhage or are associated with fibrous proliferation, retinal edema, retinal/vitreous hemorrhage or traction retinal detachments may occur resulting in potentially catastrophic loss of vision. While many factors can stimulate endothelial cells to proliferate, the cells ultimately must navigate the ECM;during normal angiogenesis this is done in a highly ordered fashion resulting in the formation of functional blood vessels. During abnormal neovascularization of the iris, retina or choroid, angiogenesis is unregulated and usually results in the formation of dysfunctional blood vessels. The long term goal of this research program has been to understand the interaction between proliferating vascular endothelial cells, adhesion receptors and various components of the ECM. More recently we have explored the role of several other cell types critical to the regulation of retinal angiogenesis. One of these cells, adult bone marrow derived lineage negative hematopoietic stem cells (Lin-HSC), exert profound vasculo- and neurotrophic rescue in models of vascular and retinal degeneration. Thus, autologous cell based therapy may be useful in the treatment degenerative of eye diseases if underlying mechanisms of angiogenesis and Lin-HSC homing were better understood. We will accomplish this through the following specific aims: (1) study the role of integrins and other adhesion receptors during ocular angiogenesis;(2) examine the mechanism whereby Lin-HSC exert vasculo- and neurotrophic rescue in several models of vascular and neural retinal degenerations;and (3) use selectively targeting HSC transfected with siRNAs and plasmids to create conditional knockdowns useful for the study of ocular angiogenesis. These studies will provide insights into mechanisms of angiogenesis that will be useful for the prevention and treatment of neovascular eye diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY011254-14S1
Application #
8005876
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
1996-03-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
14
Fiscal Year
2010
Total Cost
$215,000
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Kurihara, Toshihide; Westenskow, Peter D; Gantner, Marin L et al. (2016) Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration. Elife 5:
Paris, Liliana P; Johnson, Caroline H; Aguilar, Edith et al. (2016) Global metabolomics reveals metabolic dysregulation in ischemic retinopathy. Metabolomics 12:15
Murinello, Salome; Moreno, Stacey K; Macauley, Matthew S et al. (2016) Assessing Retinal Microglial Phagocytic Function In Vivo Using a Flow Cytometry-based Assay. J Vis Exp :
Barnett, Faith H; Rosenfeld, Mauricio; Wood, Malcolm et al. (2016) Macrophages form functional vascular mimicry channels in vivo. Sci Rep 6:36659

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