Avascularity of the cornea is necessary for optical transparency in the visual axis. Vision-threatening corneal angiogenesis can be caused by diseases, aging, infection, or trauma. The basis of the cornea's physiological avascularity remains to be elucidated. This proposal will apply RNA interference, a promising new efficient &specific molecular technology that targets specific mRNAs, to elucidate mediators and mechanisms of normal corneal avascularity. We hypothesize that corneal avascularity is maintained at least in part by extracellular soluble VEGF receptor-1 (sVEGFR-1) Our specific aims are to test the hypotheses that: 1. To rigorously determine if adult corneal avascularity requires sFlt-1. 2. To determine whether selective genetic ablation of sFlt-1 in the corneal epithelium induces corneal vascularization. 3. To determine the expression profile of sFlt-1 in Pax6 and cornl mice with spontaneous corneal vascularization and whether sFlt-1 can restore corneal avascularity in Pax61 and cornl in these mice. This line of inquiry will have broad relevance to public health. The cornea is commonly used as a platform for testing the efficacy of anti-angiogenic therapies for use in cancer, macular degeneration, and diabetes. Understanding the molecular basis of how the cornea normally maintains its avascularity will have significant ramifications for the reliance on and validity of such anti-angiogenesis efficacy studies. Furthermore, sVEGFR-1 plays a pathogenic role in pre-eclampsia, lupus, and certain nephropathies. Our development of an siRNA against VEGFR-1 may eventually be of benefit for the management of these disorders, and it may also prove valuable in promoting beneficial angiogenesis, e.g., in stroke &heart disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017950-05
Application #
8268454
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$321,829
Indirect Cost
$107,989
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lambert, Nathan G; ElShelmani, Hanan; Singh, Malkit K et al. (2016) Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res 54:64-102
Yasuma, Reo; Cicatiello, Valeria; Mizutani, Takeshi et al. (2016) Intravenous immune globulin suppresses angiogenesis in mice and humans. Signal Transduct Target Ther 1:
Bogdanovich, Sasha; Kim, Younghee; Mizutani, Takeshi et al. (2016) Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther 1:
Cahoon, Judd M; Rai, Ruju R; Carroll, Lara S et al. (2015) Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy. Diabetes 64:4247-59
Bosco, Alejandra; Romero, Cesar O; Ambati, Balamurali K et al. (2015) In vivo dynamics of retinal microglial activation during neurodegeneration: confocal ophthalmoscopic imaging and cell morphometry in mouse glaucoma. J Vis Exp :e52731
Uehara, Hironori; Mamalis, Christina; McFadden, Molly et al. (2015) The reduction of serum soluble Flt-1 in patients with neovascular age-related macular degeneration. Am J Ophthalmol 159:92-100.e1-2
Bosco, Alejandra; Romero, Cesar O; Breen, Kevin T et al. (2015) Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis Model Mech 8:443-55
Das, Subrata K; Gupta, Isha; Cho, Yang Kyung et al. (2014) Vimentin knockdown decreases corneal opacity. Invest Ophthalmol Vis Sci 55:4030-40
Hirano, Yoshio; Yasuma, Tetsuhiro; Mizutani, Takeshi et al. (2014) IL-18 is not therapeutic for neovascular age-related macular degeneration. Nat Med 20:1372-5
Kim, Younghee; Tarallo, Valeria; Kerur, Nagaraj et al. (2014) DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc Natl Acad Sci U S A 111:16082-7

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