Corneal angiogenesis is driven by VEGF and is a key pathogenic event in rejection of corneal transplants, injury, and ocular surface diseases. VEGF autocrine loops have been demonstrated in vascular endothelial cells;further, VEGF can upregulate its own receptor VEGFR-2. Intracellular autocrine loops would render cells resistant to modalities targeting VEGF extracellularly. Disruption of intracellular VEGF signaling may represent a powerful addition to the anti-angiogenic arsenal, by sabotaging VEGF secretion and intracellular autocrine loops. This proposal aims to disrupt both VEGF and VEGFR-2 expression intracellularly, which may represent an important modality in treating disorders involving angiogenesis, in vascular endothelial cells in vitro and in the injured cornea in vivo. We hypothesize intracellular autocrine loops are part of VEGF signaling in cornea and that expression of """"""""intraceptors"""""""", recombinant protein constructs of subunits of the high-affinity VEGF receptor 1 (FIT) coupled with the endoplasmic reticulum retention signal sequence KDEL, will inhibit angiogenesis by targeting VEGF and VEGFR-2.
Our specific aims are: 1. To determine whether intraceptors regress corneal neovascularization and if FU24K suppresses VEGFR- 2 expression and angiogenic events in HMEC by heterodimerization. 2. To determine the mechanisms of intraceptor action by analyzing if they induce: unfolded protein response (DPR) (evidenced by elevated ATF6a and XBP-1) apoptosis of vascular endothelial cells suppression of Ets-1 &MMP-1, phosphorylation of FAK, and DNA synthesis (physiologically mediated by native Flt/VEGFR-2 heterodimers which we expect would not be formed in presence of intraceptors) 3. To determine whether long-term expression of intraceptors can be achieved using plasmids directing their expression encapsulated in PLGA nanoparticles.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017182-04
Application #
7809474
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2007-04-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$371,622
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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