The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and associated retinal edema, hemorrhage and gliosis. The research program supported by this grant for the past 15 years initially focused on understanding the role of adhesion receptors (e.g., integrins) in ocular angiogenesis and developing ways to inhibit abnormal neovascularization. Several years ago, we indentified and characterized endothelial and myeloid progenitor cells as potential therapeutics useful for vascular- and neurotrophic rescue in the treatment of retinal vascular and neuronal degenerative diseases. By studying the fates of these progenitor cells after implantation into eyes of rodent models of retinal disease, we indentified additional cell populations (e.g., microglia, astrocytes, Muller glia) critical to maintaining normal vascular and neuronal networks in the retina. In the next project period, we will continue our studies on mechanisms of basic retinal angiogenesis, developing approaches to inhibit abnormal vessel growth and understanding paracrine effects of endothelium and glia on neuronal parenchyma. We will use novel Cre-inducible transgenic mice in which we have deleted selected angiogenesis-associated genes in specific cell types. The development of the retinal, as well as regression of the hyaloidal, vasculature will be studied in these mice under normal and hypoxic conditions. We will also assess the effect of injected and novel cell-based delivery systems for the delivery of combination angiostatic and neurotrophic therapies in models of retinal neovascularization. The overarching hypothesis driving this research program is that physiological angiogenesis differs from pathological angiogenesis largely as a result of "miscues" between interacting cell populations and their micro-environments;while the principle participant is the endothelial cell, other cells are critical to vessel formation and these include microglia, inflammatory cells and even neurons. We will continue to explore the relationship between these cells types, how they influence the extracellular matrix (e.g., "microenvironment") and what molecules they influence during "cross-talk". This will be accomplished through the following Specific Aims: (1) We will explore the potential utility of combination angiostatic therapy and targeted cell-based delivery of angiostatics and neurotrophics in treating ocular neovascularization;(2) We will explore and define the role of non-endothelial cells in retinal angiogenesis and vascular regression;and (3) Using novel metabolomic analyses we will identify molecules associated with hypoxia driven angiogenesis in physiologically relevant models of angiogenesis.

Public Health Relevance

The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal blood vessel growth (angiogenesis) and associated retinal edema, hemorrhage and gliosis. Using rodent models of retinal vascular diseases such as diabetic retinopathy and age related macular degeneration, we will explore the utility of novel anti-angiogenic and neurotrophic drugs for the treatment of retinal vascular and neuronal degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011254-17
Application #
8625754
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Shen, Grace L
Project Start
1996-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
17
Fiscal Year
2014
Total Cost
$734,251
Indirect Cost
$333,323
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Westenskow, Peter D; Kurihara, Toshihide; Friedlander, Martin (2014) Utilizing stem cell-derived RPE cells as a therapeutic intervention for age-related macular degeneration. Adv Exp Med Biol 801:323-9
Kurihara, Toshihide; Westenskow, Peter D; Friedlander, Martin (2014) Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signaling in the retina. Adv Exp Med Biol 801:275-81
Michael, Iacovos P; Westenskow, Peter D; Hacibekiroglu, Sabiha et al. (2014) Local acting Sticky-trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye. EMBO Mol Med 6:604-23
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Westenskow, Peter D; Kurihara, Toshihide; Aguilar, Edith et al. (2013) Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. J Clin Invest 123:4900-8
Ukrohne, Tim U; Westenskow, Peter D; Kurihara, Toshihide et al. (2012) Generation of retinal pigment epithelial cells from small molecules and OCT4 reprogrammed human induced pluripotent stem cells. Stem Cells Transl Med 1:96-109
Kurihara, Toshihide; Westenskow, Peter D; Krohne, Tim U et al. (2011) Astrocyte pVHL and HIF-* isoforms are required for embryonic-to-adult vascular transition in the eye. J Cell Biol 195:689-701
Weidemann, Alexander; Krohne, Tim U; Aguilar, Edith et al. (2010) Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia 58:1177-85
Dorrell, Michael I; Aguilar, Edith; Jacobson, Ruth et al. (2010) Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy. Glia 58:43-54
Marchetti, Valentina; Krohne, Tim U; Friedlander, David F et al. (2010) Stemming vision loss with stem cells. J Clin Invest 120:3012-21

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