Angiogenesis is a common pathological finding in such diverse conditions as proliferative diabetic retinopathy, neovascular glaucoma, interstital keratitis, rheumatoid arthritis, and cancer. The inhibition of pathological angiogenesis is, therefore, clinically relevant to ophthalmology, as well as other medical specialties. The overall goal of this research proposal is to increase our understanding of the endogenous inhibition of ocular angiogenesis. The working hypothesis is that the avascular structures of the eye contain one or more endogenous inhibitors of angiogenesis that serve to counteract the angiogenesis simulators normally present in these tissues. The presence and degree of vascularization in ocular tissues may depend on a fine balance between angiogenesis stimulation and inhibition.
The specific aims of this research proposal are designed to answer several basic questions about the presence, identity, and distribution of endogenous angiogenesis inhibitors in the eye. Additionally, we will attempt to modulate the angiogenic activity of corneas used for transplantation. In brief, we propose to (1) complete the purification and identification of a new angiogenesis inhibitor derived from bovine cornea, (2) survey ocular fluids and tissues using immunoblotting, immunolocalization, and in vivo bioassays to identify and localize endogenous angiogenesis inhibitors, and (3) develop a corneal storage solution that decreases the endogenous angiogenic activity of the cornea. The latter involves two modifications of a known corneal storage solution: (a) the addition of agents that extract endogenous angiogenic bFGF from corneas (e.g. cyclodextrin) and; (b) the addition of non-toxic inhibitors of angiogenesis (e.g. AGM-1470). It is envisioned that any molecule(s) and/or principles uncovered that are responsible for the inhibition of angiogenesis in the eye may be used in the future treatment of ocular and systemic angiogenic diseases. Such strategies may include the local or systemic administration of one or more non-toxic naturally- occurring angiogenesis inhibitors. The opportunity to carry out this research program, along with the opportunity to receive formal training in biochemistry, cell biology, and molecular biology, will further the applicant toward his goal of becoming an independent investigator.
