The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis. Pathological retinal or choroidal neovascularization lead to visual loss in diabetic retinopathy (DR) and age related macular degeneration (ARMD), respectively. While inhibition of abnormal angiogenesis would not necessarily cure the underlying diseases, it would preserve vision by preventing complications associated with neovascularization such as hemorrhage and edema. We have been studying the anti-angiogenic activity of fragments of tryptophanyl-tRNA synthetase (TrpRS). In normal human cells TrpRS exists as both the full length form and a truncated form (mini-TrpRS) in which an amino-terminal domain is deleted due to alternative splicing of the pre-mRNA. This latter form is preferentially synthesized in cells exposed to interferon-w. Further truncation of mini-TrpRS results in a 42 kD form (T2) that is the most potent of the angiostatic forms of TrpRS evaluated to date. ? ? In this application we propose to further characterize the anti-angiogenic activity of TrpRS fragments and identify a candidate drug and delivery system for use in clinical trials of neovascular eye diseases. Specifically, we will: (1) examine the physiological role of TrpRS fragments in the regulation of normal and abnormal ocular angiogenesis; (2) identify and characterize the retinal receptor to which these fragments bind; (3) characterize the structural aspects of TrpRS fragments with anti-angiogenic activity and use this information to model small molecular antagonists with similar activity; (4) develop viral-, cell- and targeted liposome-based vectors for the delivery of T2 to inhibit ocular neovascularization in a variety of animal models; and (5) begin pharmacokinetic and toxicology studies on these vector, recombinant protein and/or small molecule therapeutics as a first step towards human clinical trials for the treatment of neovascular eye diseases such as neovascular ARMD, proliferative DR and rubeotic glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
5R24EY014174-02
Application #
6647101
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
2002-08-15
Project End
2007-07-31
Budget Start
2003-09-08
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$1,930,367
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Scheppke, Lea; Aguilar, Edith; Gariano, Ray F et al. (2008) Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. J Clin Invest 118:2337-46
Nepomuceno, Ronald R; Pache, Lars; Nemerow, Glen R (2007) Enhancement of gene transfer to human myeloid cells by adenovirus-fiber complexes. Mol Ther 15:571-8
Iacobelli-Martinez, Milena; Nemerow, Glen R (2007) Preferential activation of Toll-like receptor nine by CD46-utilizing adenoviruses. J Virol 81:1305-12
Dorrell, Michael I; Aguilar, Edith; Scheppke, Lea et al. (2007) Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci U S A 104:967-72
Banin, Eyal; Dorrell, Michael I; Aguilar, Edith et al. (2006) T2-TrpRS inhibits preretinal neovascularization and enhances physiological vascular regrowth in OIR as assessed by a new method of quantification. Invest Ophthalmol Vis Sci 47:2125-34
Dorrell, Michael I; Friedlander, Martin (2006) Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina. Prog Retin Eye Res 25:277-95
Ritter, Matthew R; Banin, Eyal; Moreno, Stacey K et al. (2006) Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest 116:3266-76
Mitra, S K; Mikolon, D; Molina, J E et al. (2006) Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene 25:5969-84
Potter, Matthew D; Barbero, Simone; Cheresh, David A (2005) Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. J Biol Chem 280:31906-12
Iacobelli-Martinez, Milena; Nepomuceno, Ronald R; Connolly, Jodi et al. (2005) CD46-utilizing adenoviruses inhibit C/EBPbeta-dependent expression of proinflammatory cytokines. J Virol 79:11259-68

Showing the most recent 10 out of 17 publications